US20230321177A1 - Polypharmaceutical drug compositions and related methods - Google Patents
Polypharmaceutical drug compositions and related methods Download PDFInfo
- Publication number
- US20230321177A1 US20230321177A1 US18/209,360 US202318209360A US2023321177A1 US 20230321177 A1 US20230321177 A1 US 20230321177A1 US 202318209360 A US202318209360 A US 202318209360A US 2023321177 A1 US2023321177 A1 US 2023321177A1
- Authority
- US
- United States
- Prior art keywords
- composition
- compounds
- polarity
- group
- curcuma longa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 154
- 238000000034 method Methods 0.000 title claims abstract description 78
- 229940079593 drug Drugs 0.000 title abstract description 44
- 239000003814 drug Substances 0.000 title description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 84
- 201000011510 cancer Diseases 0.000 claims abstract description 33
- 244000163122 Curcuma domestica Species 0.000 claims description 59
- 239000002904 solvent Substances 0.000 claims description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims description 47
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 46
- 235000003373 curcuma longa Nutrition 0.000 claims description 43
- 108090000623 proteins and genes Proteins 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- XOCANRBEOZQNAQ-KBPBESRZSA-N alpha-turmerone Natural products O=C(/C=C(\C)/C)C[C@H](C)[C@H]1C=CC(C)=CC1 XOCANRBEOZQNAQ-KBPBESRZSA-N 0.000 claims description 28
- 102000004169 proteins and genes Human genes 0.000 claims description 24
- 210000004027 cell Anatomy 0.000 claims description 23
- 229940109262 curcumin Drugs 0.000 claims description 23
- 239000004148 curcumin Substances 0.000 claims description 23
- 235000012754 curcumin Nutrition 0.000 claims description 23
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 23
- 229920001282 polysaccharide Polymers 0.000 claims description 23
- 239000005017 polysaccharide Substances 0.000 claims description 23
- NAAJVHHFAXWBOK-ZDUSSCGKSA-N (+)-(S)-ar-turmerone Chemical compound CC(C)=CC(=O)C[C@H](C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-ZDUSSCGKSA-N 0.000 claims description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 18
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 17
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 17
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 17
- 235000013824 polyphenols Nutrition 0.000 claims description 17
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
- 150000003505 terpenes Chemical class 0.000 claims description 17
- XOCANRBEOZQNAQ-KGLIPLIRSA-N ar-turmerone Natural products C[C@H](CC(=O)C=C(C)C)[C@@H]1CC=C(C)C=C1 XOCANRBEOZQNAQ-KGLIPLIRSA-N 0.000 claims description 15
- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 claims description 14
- HJTVQHVGMGKONQ-LUZURFALSA-N Curcumin II Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 claims description 14
- 208000006994 Precancerous Conditions Diseases 0.000 claims description 14
- JYTVKRNTTALBBZ-UHFFFAOYSA-N bis demethoxycurcumin Natural products C1=CC(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=CC(O)=C1 JYTVKRNTTALBBZ-UHFFFAOYSA-N 0.000 claims description 14
- PREBVFJICNPEKM-YDWXAUTNSA-N bisdemethoxycurcumin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C=C1 PREBVFJICNPEKM-YDWXAUTNSA-N 0.000 claims description 14
- JIJQKFPGBBEJNF-UHFFFAOYSA-N curlone Chemical compound CC(C)=CC(=O)CC(C)C1CCC(=C)C=C1 JIJQKFPGBBEJNF-UHFFFAOYSA-N 0.000 claims description 14
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 claims description 14
- YXAKCQIIROBKOP-UHFFFAOYSA-N di-p-hydroxycinnamoylmethane Natural products C=1C=C(O)C=CC=1C=CC(=O)C=C(O)C=CC1=CC=C(O)C=C1 YXAKCQIIROBKOP-UHFFFAOYSA-N 0.000 claims description 14
- 238000009169 immunotherapy Methods 0.000 claims description 14
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 claims description 14
- XOCANRBEOZQNAQ-UHFFFAOYSA-N α-turmerone Chemical compound CC(C)=CC(=O)CC(C)C1CC=C(C)C=C1 XOCANRBEOZQNAQ-UHFFFAOYSA-N 0.000 claims description 14
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 10
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 10
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims description 8
- 230000008595 infiltration Effects 0.000 claims description 7
- 238000001764 infiltration Methods 0.000 claims description 7
- 208000002741 leukoplakia Diseases 0.000 claims description 7
- 238000002512 chemotherapy Methods 0.000 claims description 6
- NAAJVHHFAXWBOK-UHFFFAOYSA-N (+)-ar-Turmerone Chemical compound CC(C)=CC(=O)CC(C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-UHFFFAOYSA-N 0.000 claims description 3
- 230000035945 sensitivity Effects 0.000 claims description 3
- 229960005486 vaccine Drugs 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims 3
- 239000012454 non-polar solvent Substances 0.000 claims 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 10
- 230000000975 bioactive effect Effects 0.000 abstract description 7
- 208000003445 Mouth Neoplasms Diseases 0.000 abstract description 5
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 abstract description 4
- 208000024891 symptom Diseases 0.000 abstract 1
- 239000000284 extract Substances 0.000 description 89
- -1 flavorings Substances 0.000 description 47
- 235000018102 proteins Nutrition 0.000 description 21
- 238000011282 treatment Methods 0.000 description 21
- 150000004804 polysaccharides Chemical class 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 201000010099 disease Diseases 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000546 pharmaceutical excipient Substances 0.000 description 16
- 241000196324 Embryophyta Species 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 239000000463 material Substances 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 229940124531 pharmaceutical excipient Drugs 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 230000001965 increasing effect Effects 0.000 description 11
- 230000007246 mechanism Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000002246 antineoplastic agent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000008901 benefit Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 7
- 229940127089 cytotoxic agent Drugs 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 239000002207 metabolite Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000003285 pharmacodynamic effect Effects 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 5
- 108010057466 NF-kappa B Proteins 0.000 description 5
- 102000003945 NF-kappa B Human genes 0.000 description 5
- 241000288906 Primates Species 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000000017 hydrogel Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102000019197 Superoxide Dismutase Human genes 0.000 description 4
- 108010012715 Superoxide dismutase Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 239000002256 antimetabolite Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 235000021323 fish oil Nutrition 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 201000010536 head and neck cancer Diseases 0.000 description 4
- 208000014829 head and neck neoplasm Diseases 0.000 description 4
- 238000010166 immunofluorescence Methods 0.000 description 4
- 230000001024 immunotherapeutic effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 229940125697 hormonal agent Drugs 0.000 description 3
- 239000000677 immunologic agent Substances 0.000 description 3
- 229940124541 immunological agent Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229920005610 lignin Polymers 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229940041616 menthol Drugs 0.000 description 3
- 229920005615 natural polymer Polymers 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 235000010603 pastilles Nutrition 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 229920000570 polyether Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- GTADQMQBQBOJIO-UHFFFAOYSA-N 1,12-Dihydroxy-1,6,12,17-tetraazacyclodocosane-2,5,13,16-tetrone Chemical compound ON1CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC1=O GTADQMQBQBOJIO-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- VHJWDTPKSIFZBV-UHFFFAOYSA-N 2,5,7-trihydroxy-4-(4-hydroxy-3,5-dimethoxy-6-methyloxan-2-yl)oxy-3,9-dimethoxy-2-methyl-3,4-dihydrotetracene-1,6,11-trione Chemical compound COC1C(O)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C(OC)C=C3C3=O)=C3C=C2C(=O)C(C)(O)C1OC VHJWDTPKSIFZBV-UHFFFAOYSA-N 0.000 description 2
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 102000004000 Aurora Kinase A Human genes 0.000 description 2
- 108090000461 Aurora Kinase A Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- 108010058546 Cyclin D1 Proteins 0.000 description 2
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 230000007067 DNA methylation Effects 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 241000522213 Dichilus lebeckioides Species 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 2
- 102100027768 Histone-lysine N-methyltransferase 2D Human genes 0.000 description 2
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 2
- 101001045848 Homo sapiens Histone-lysine N-methyltransferase 2B Proteins 0.000 description 2
- 101001008894 Homo sapiens Histone-lysine N-methyltransferase 2D Proteins 0.000 description 2
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004721 Polyphenylene oxide Substances 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- RKJCLPSFLUKWQY-UHFFFAOYSA-N Tricrozarin A Chemical compound OC1=C2C(=O)C(OC)=C(OC)C(=O)C2=C(O)C2=C1OCO2 RKJCLPSFLUKWQY-UHFFFAOYSA-N 0.000 description 2
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- ANVAOWXLWRTKGA-XHGAXZNDSA-N all-trans-alpha-carotene Chemical compound CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1C(C)=CCCC1(C)C ANVAOWXLWRTKGA-XHGAXZNDSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 230000002886 autophagic effect Effects 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000002705 metabolomic analysis Methods 0.000 description 2
- 230000001431 metabolomic effect Effects 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical class CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 239000000419 plant extract Substances 0.000 description 2
- 230000004983 pleiotropic effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 208000017572 squamous cell neoplasm Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 235000020138 yakult Nutrition 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- LLWMPGSQZXZZAE-JZFVXYNCSA-N (1s,2s,4ar,4bs,7s,8ar,10ar)-7-hydroxy-2,4b,7',8,8,10a-hexamethylspiro[2,3,4,4a,5,6,7,8a,9,10-decahydrophenanthrene-1,2'-3h-1-benzofuran]-4',5'-dione Chemical compound C1C(C(C(=O)C=C2C)=O)=C2O[C@]21[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1CC[C@@H]2C LLWMPGSQZXZZAE-JZFVXYNCSA-N 0.000 description 1
- JLSPXOVSIVYMCY-UHFFFAOYSA-N (2,4-dichlorophenyl)methyl thiocyanate Chemical compound ClC1=CC=C(CSC#N)C(Cl)=C1 JLSPXOVSIVYMCY-UHFFFAOYSA-N 0.000 description 1
- PQZVBIJEPVKNOZ-PCLZMVHQSA-N (2R)-2-[(1S)-1-hydroxy-1-[(5R,6R,8R,9S,10R,13S,14R,17S)-5,6,14,17-tetrahydroxy-10,13-dimethyl-1-oxo-6,7,8,9,11,12,15,16-octahydro-4H-cyclopenta[a]phenanthren-17-yl]ethyl]-4,5-dimethyl-2,3-dihydropyran-6-one Chemical class C1C(C)=C(C)C(=O)O[C@H]1[C@](C)(O)[C@@]1(O)[C@@]2(C)CC[C@@H]3[C@@]4(C)C(=O)C=CC[C@]4(O)[C@H](O)C[C@H]3[C@]2(O)CC1 PQZVBIJEPVKNOZ-PCLZMVHQSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KZMHNEBMQDBQND-LBNZKSCFSA-N (2e,5s,6r,7s,9s,10e,12e,15r,16z,18e)-17-ethyl-6-hydroxy-9-(hydroxymethyl)-3,5,7,11,15-pentamethyl-19-[(2s,3s)-3-methyl-6-oxo-2,3-dihydropyran-2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid Chemical compound OC(=O)/C=C(C)/C[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](CO)/C=C(\C)/C=C/C[C@@H](C)/C=C(/CC)\C=C\[C@@H]1OC(=O)C=C[C@@H]1C KZMHNEBMQDBQND-LBNZKSCFSA-N 0.000 description 1
- OKNKQPUDKRCBIK-MAVIPZKQSA-N (2r,3r,4s,5s)-2-(9-hydroxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-2-ium-2-yl)oxane-3,4,5-triol;bromide Chemical compound [Br-].C=1C=C2C(C)=C3NC4=CC=C(O)C=C4C3=C(C)C2=C[N+]=1[C@@H]1OC[C@H](O)[C@H](O)[C@H]1O OKNKQPUDKRCBIK-MAVIPZKQSA-N 0.000 description 1
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 1
- JAUGQKWRVWARPG-GFOUHAFJSA-N (2s)-2-[(3s)-1-[(2s,3s,4s,6r)-6-[[(1s,3s)-3-acetyl-3,5,10,12-tetrahydroxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]-4-amino-2-methyloxan-3-yl]oxy-3-hydroxybutoxy]propanal Chemical compound O1[C@@H](C)[C@@H](OC(O[C@@H](C)C=O)C[C@@H](O)C)[C@@H](N)C[C@@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 JAUGQKWRVWARPG-GFOUHAFJSA-N 0.000 description 1
- QJERBBQXOMUURJ-INIZCTEOSA-N (2s)-2-[(4-chlorobenzoyl)amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C1=CC=C(Cl)C=C1 QJERBBQXOMUURJ-INIZCTEOSA-N 0.000 description 1
- ZUQBAQVRAURMCL-CVRLYYSRSA-N (2s)-2-[[4-[2-(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2CC1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-CVRLYYSRSA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-N 0.000 description 1
- YEORLXJBCPPSOC-SSDOTTSWSA-N (2s)-2-amino-5-(diaminomethylideneamino)-2-(difluoromethyl)pentanoic acid Chemical compound NC(=N)NCCC[C@@](N)(C(F)F)C(O)=O YEORLXJBCPPSOC-SSDOTTSWSA-N 0.000 description 1
- JEMVIRAQUIJOCL-XURVNGJNSA-N (3r,4ar,12bs)-4a,8,12b-trihydroxy-9-[(2r,4r,5s,6r)-4-hydroxy-6-methyl-5-[(2s,5s,6s)-6-methyl-5-[(2r,6s)-6-methyl-5-oxooxan-2-yl]oxyoxan-2-yl]oxyoxan-2-yl]-3-methyl-3-[(2s,5s,6s)-6-methyl-5-[(2r,6s)-6-methyl-5-oxooxan-2-yl]oxyoxan-2-yl]oxy-2,4-dihydrobenzo Chemical compound O([C@H]1CC[C@@H](O[C@H]1C)O[C@H]1[C@@H](C[C@@H](O[C@@H]1C)C=1C(=C2C(=O)C3=C([C@]4(C(=O)C[C@@](C)(C[C@@]4(O)C=C3)O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)C(=O)CC4)CC3)O)C(=O)C2=CC=1)O)O)[C@H]1CCC(=O)[C@H](C)O1 JEMVIRAQUIJOCL-XURVNGJNSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- JEZZKSQFJNWDCY-NSIKDUERSA-N (8z)-2-[3,4-dihydroxy-4,6-dimethyl-5-(methylamino)oxan-2-yl]oxy-8-propylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=C2C(=O)N3CC(=C/CC)\CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-NSIKDUERSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- AJMWJDGKNKNYEW-WYMLVPIESA-N (e)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methylprop-2-en-1-one Chemical compound COC1=CC=C(OC)C(C(=O)C(\C)=C\C=2C=CC(=CC=2)N(C)C)=C1 AJMWJDGKNKNYEW-WYMLVPIESA-N 0.000 description 1
- OQMYRVPMCIOFHL-GCOHUWJYSA-N (e)-3-[(6r)-6-hydroxy-4-methoxy-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]-n,n-dimethylprop-2-enamide Chemical compound N1[C@H](O)C2CC(\C=C\C(=O)N(C)C)=CN2C(=O)C2=C1C(OC)=CC=C2 OQMYRVPMCIOFHL-GCOHUWJYSA-N 0.000 description 1
- ZTXDHEQQZVFGPK-UHFFFAOYSA-N 1,2,4-tris(oxiran-2-ylmethyl)-1,2,4-triazolidine-3,5-dione Chemical compound C1OC1CN1C(=O)N(CC2OC2)C(=O)N1CC1CO1 ZTXDHEQQZVFGPK-UHFFFAOYSA-N 0.000 description 1
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2r)-oxiran-2-yl]methyl]-3-[[(2s)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- KHWIRCOLWPNBJP-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2,6-dioxopiperidin-3-yl)-1-nitrosourea Chemical compound ClCCN(N=O)C(=O)NC1CCC(=O)NC1=O KHWIRCOLWPNBJP-UHFFFAOYSA-N 0.000 description 1
- YJZJEQBSODVMTH-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea Chemical compound OCCNC(=O)N(N=O)CCCl YJZJEQBSODVMTH-UHFFFAOYSA-N 0.000 description 1
- BQIFCAGMUAMYDV-DHBOJHSNSA-N 1-(2-chloroethyl)-3-[(2r,6s)-2,6-dihydroxycyclohexyl]-1-nitrosourea Chemical compound O[C@H]1CCC[C@@H](O)C1NC(=O)N(CCCl)N=O BQIFCAGMUAMYDV-DHBOJHSNSA-N 0.000 description 1
- RCLLNBVPCJDIPX-UHFFFAOYSA-N 1-(2-chloroethyl)-3-[2-(dimethylsulfamoyl)ethyl]-1-nitrosourea Chemical compound CN(C)S(=O)(=O)CCNC(=O)N(N=O)CCCl RCLLNBVPCJDIPX-UHFFFAOYSA-N 0.000 description 1
- ICAYNKLSQSKOJZ-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-[(4-fluorophenyl)-hydroxymethyl]piperidin-1-yl]butan-1-one Chemical compound C=1C=C(F)C=CC=1C(O)C(CC1)CCN1CCCC(=O)C1=CC=C(F)C=C1 ICAYNKLSQSKOJZ-UHFFFAOYSA-N 0.000 description 1
- MAUYWACILHVRLR-UHFFFAOYSA-N 1-(morpholin-4-ylmethyl)-4-[2-[4-(morpholin-4-ylmethyl)-3,5-dioxopiperazin-1-yl]propyl]piperazine-2,6-dione Chemical compound C1C(=O)N(CN2CCOCC2)C(=O)CN1C(C)CN(CC1=O)CC(=O)N1CN1CCOCC1 MAUYWACILHVRLR-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- VSWUWZJXMRATTF-UHFFFAOYSA-N 1-propan-2-yl-1h-pyrrolizine Chemical compound C1=CC=C2C(C(C)C)C=CN21 VSWUWZJXMRATTF-UHFFFAOYSA-N 0.000 description 1
- AQBUFJBHZGRZRV-NCIKYIMWSA-N 10-[(2R,4S,5S,6S)-4-(dimethylamino)-5-hydroxy-4,6-dimethyloxan-2-yl]-11-hydroxy-5-methyl-2-[(2R,3S)-2-methyl-3-[(2R,3S)-3-methyloxiran-2-yl]oxiran-2-yl]naphtho[2,3-h]chromene-4,7,12-trione Chemical compound C[C@@H]1O[C@H]1[C@H]1[C@@](C=2OC3=C4C(=O)C5=C(O)C([C@@H]6O[C@@H](C)[C@@H](O)[C@](C)(C6)N(C)C)=CC=C5C(=O)C4=CC(C)=C3C(=O)C=2)(C)O1 AQBUFJBHZGRZRV-NCIKYIMWSA-N 0.000 description 1
- SCWWNJYIUMBQKK-UHFFFAOYSA-N 10-[4-(dimethylamino)-5,6-dihydroxy-4,6-dimethyloxan-2-yl]-8-[4-(dimethylamino)-5-hydroxy-6-methyloxan-2-yl]-2-[3-(3,3-dimethyloxiran-2-yl)-2-methyloxiran-2-yl]-11-hydroxy-5-methylnaphtho[2,3-h]chromene-4,7,12-trione Chemical compound C1C(N(C)C)C(O)C(C)OC1C1=CC(C2OC(C)(O)C(O)C(C)(C2)N(C)C)=C(O)C2=C1C(=O)C(C=C(C)C=1C(C=C(OC3=1)C1(C)C(O1)C1C(O1)(C)C)=O)=C3C2=O SCWWNJYIUMBQKK-UHFFFAOYSA-N 0.000 description 1
- CNQCTSLNJJVSAU-UHFFFAOYSA-N 132937-89-4 Chemical compound O.Cl.Cl.Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO CNQCTSLNJJVSAU-UHFFFAOYSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- LAINPTZBIXYTIZ-UHFFFAOYSA-N 2-(3-hydroxy-2,4,5,7-tetraiodo-6-oxo-9-xanthenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C(O)=C(I)C=C21 LAINPTZBIXYTIZ-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N 2-Aminobutanoic acid Natural products CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- HGLRIYIVJRXBQM-UHFFFAOYSA-N 2-[2-[amino-[bis(2-chloroethyl)amino]phosphoryl]oxyethyl]-1,3-thiazinane-4-carboxylic acid Chemical compound ClCCN(CCCl)P(=O)(N)OCCC1NC(C(O)=O)CCS1 HGLRIYIVJRXBQM-UHFFFAOYSA-N 0.000 description 1
- JSPUCPNQXKTYRO-LWILDLIXSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol Chemical compound C([C@@]1(C)[C@H]2[C@](C(=CCC2)C)(C)CC[C@@H]1C)C1=CC(O)=CC=C1O JSPUCPNQXKTYRO-LWILDLIXSA-N 0.000 description 1
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- AKSIYNOQZYMJED-UHFFFAOYSA-N 2-amino-4-(aminomethoxy)butanoic acid Chemical compound NCOCCC(N)C(O)=O AKSIYNOQZYMJED-UHFFFAOYSA-N 0.000 description 1
- LHNIUFUSFGYJEO-UHFFFAOYSA-N 2-amino-5-phenylsulfanyl-1h-indole-3-carbonitrile Chemical compound C1=C2C(C#N)=C(N)NC2=CC=C1SC1=CC=CC=C1 LHNIUFUSFGYJEO-UHFFFAOYSA-N 0.000 description 1
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 description 1
- NADDOZUGAJXMGT-UHFFFAOYSA-Q 2-diphenylphosphaniumylethyl(diphenyl)phosphanium gold(1+) chloride Chemical compound Cl[Au].C(C[PH+](c1ccccc1)c1ccccc1)[PH+](c1ccccc1)c1ccccc1.C(C[PH+](c1ccccc1)c1ccccc1)[PH+](c1ccccc1)c1ccccc1 NADDOZUGAJXMGT-UHFFFAOYSA-Q 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- RBFPKTBMLPIPMA-UHFFFAOYSA-N 2-methyl-n-phenylacridin-1-amine Chemical compound CC1=CC=C2N=C3C=CC=CC3=CC2=C1NC1=CC=CC=C1 RBFPKTBMLPIPMA-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- HQLHJCFATKAUSO-UHFFFAOYSA-N 3,7-dihydroxytropolone Chemical compound OC1=CC=CC(=O)C(O)=C1O HQLHJCFATKAUSO-UHFFFAOYSA-N 0.000 description 1
- IOSAAWHGJUZBOG-UHFFFAOYSA-N 3-(6-amino-9h-purin-9-yl)nonan-2-ol Chemical compound N1=CN=C2N(C(C(C)O)CCCCCC)C=NC2=C1N IOSAAWHGJUZBOG-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- MIEMDQVNFRNROW-UHFFFAOYSA-N 3-[[5-[10-[4-(dimethylamino)-5-hydroxy-4,6-dimethyloxan-2-yl]-8-[4-(dimethylamino)-5-hydroxy-6-methyloxan-2-yl]-11-hydroxy-5-methyl-2-[2-methyl-3-(3-methyloxiran-2-yl)oxiran-2-yl]-4,7-dioxo-12h-naphtho[3,2-h]chromen-12-yl]-1-hydroxypyrrole-2-carbonyl]amin Chemical compound CC1OC1C1C(C=2OC3=C4C(C=5N(C(C(=O)NCCC(O)=O)=CC=5)O)C5=C(O)C(C6OC(C)C(O)C(C)(C6)N(C)C)=CC(=C5C(=O)C4=CC(C)=C3C(=O)C=2)C2OC(C)C(O)C(C2)N(C)C)(C)O1 MIEMDQVNFRNROW-UHFFFAOYSA-N 0.000 description 1
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 1
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- WFWMIUSHSIJAKH-DBRKOABJSA-N 4-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1-oxido-1,2,4-triazin-1-ium-3-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=[N+]([O-])C=C1 WFWMIUSHSIJAKH-DBRKOABJSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-ABYLTEMBSA-N 4-[(2s,3s,4s)-3-hydroxy-2-methyl-6-[[(1s,3s)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]oxan-4-yl]morpholine-3-carbonitrile Chemical compound N1([C@H]2CC(O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-ABYLTEMBSA-N 0.000 description 1
- QGMGHALXLXKCBD-UHFFFAOYSA-N 4-amino-n-(2-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1=CC=CC=C1N QGMGHALXLXKCBD-UHFFFAOYSA-N 0.000 description 1
- NUFNKYNBZYIQDG-UHFFFAOYSA-N 5-[4-[benzyl(methyl)amino]-3-nitrophenyl]-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C(C=C1[N+]([O-])=O)=CC=C1N(C)CC1=CC=CC=C1 NUFNKYNBZYIQDG-UHFFFAOYSA-N 0.000 description 1
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- ISBUYSPRIJRBKX-UHFFFAOYSA-N 5-methyl-2-(2-naphthalen-2-yloxyethyl)-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1CCOC1=CC=C(C=CC=C2)C2=C1 ISBUYSPRIJRBKX-UHFFFAOYSA-N 0.000 description 1
- SCUPIRGJNHINID-UHFFFAOYSA-N 5-o-[2-[benzyl(methyl)amino]ethyl] 3-o-methyl 2,6-dimethyl-4-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CC(C)C1=NN2C=CC=CC2=C1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OCCN(C)CC1=CC=CC=C1 SCUPIRGJNHINID-UHFFFAOYSA-N 0.000 description 1
- MMRCWWRFYLZGAE-ZBZRSYSASA-N 533u947v6q Chemical compound O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O MMRCWWRFYLZGAE-ZBZRSYSASA-N 0.000 description 1
- VJXSSYDSOJBUAV-UHFFFAOYSA-N 6-(2,5-dimethoxy-benzyl)-5-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine Chemical compound COC1=CC=C(OC)C(CC=2C(=C3C(N)=NC(N)=NC3=NC=2)C)=C1 VJXSSYDSOJBUAV-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- LJIRBXZDQGQUOO-KVTDHHQDSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one Chemical compound C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LJIRBXZDQGQUOO-KVTDHHQDSA-N 0.000 description 1
- 102100037685 60S ribosomal protein L22 Human genes 0.000 description 1
- 102100026750 60S ribosomal protein L5 Human genes 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- PQMIPLRIRFVQJZ-QBYYVRQOSA-N 7-[2-[(2s,4s)-4-[(2r,3r,4r,5s,6s)-3-fluoro-4,5-dihydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethoxy]-7-oxoheptanoic acid Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)COC(=O)CCCCCC(O)=O)[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@H]1F PQMIPLRIRFVQJZ-QBYYVRQOSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-HQCWYSJUSA-N 7-hydroxystaurosporine Chemical compound N([C@H](O)C1=C2C3=CC=CC=C3N3C2=C24)C(=O)C1=C2C1=CC=CC=C1N4[C@H]1C[C@@H](NC)[C@@H](OC)[C@]3(C)O1 PBCZSGKMGDDXIJ-HQCWYSJUSA-N 0.000 description 1
- MNVCNERGJZWWAO-UHFFFAOYSA-N 7-piperidin-1-yl-5,10-dihydro-3h-imidazo[2,1-b]quinazolin-2-one Chemical compound C=1C=C2NC3=NC(=O)CN3CC2=CC=1N1CCCCC1 MNVCNERGJZWWAO-UHFFFAOYSA-N 0.000 description 1
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- PBCZSGKMGDDXIJ-UHFFFAOYSA-N 7beta-hydroxystaurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3C(O)NC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 PBCZSGKMGDDXIJ-UHFFFAOYSA-N 0.000 description 1
- SRIOCKJKFXAKHK-UHFFFAOYSA-N 8-amino-10h-isoindolo[1,2-b]quinazolin-12-one Chemical compound C1=CC=C2C3=NC4=CC=C(N)C=C4CN3C(=O)C2=C1 SRIOCKJKFXAKHK-UHFFFAOYSA-N 0.000 description 1
- OWWBUEMWTMDEBK-UHFFFAOYSA-N 9-acetyl-7-[4-amino-5-[3-hydroxy-1-(3-hydroxy-5-oxohexan-2-yl)oxybutoxy]-6-methyloxan-2-yl]oxy-4,6,9,11-tetrahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O1C(C)C(OC(OC(C)C(O)CC(C)=O)CC(O)C)C(N)CC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 OWWBUEMWTMDEBK-UHFFFAOYSA-N 0.000 description 1
- 102100034580 AT-rich interactive domain-containing protein 1A Human genes 0.000 description 1
- 102100030835 AT-rich interactive domain-containing protein 5B Human genes 0.000 description 1
- 102000000872 ATM Human genes 0.000 description 1
- 101150020330 ATRX gene Proteins 0.000 description 1
- 229930191984 Actinoplanone Natural products 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102100034134 Activin receptor type-1B Human genes 0.000 description 1
- 102100021886 Activin receptor type-2A Human genes 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- BGYNLOSBKBOJJD-IUCAKERBSA-N Aeroplysinin 1 Chemical class COC1=C(Br)[C@H](O)[C@](O)(CC#N)C=C1Br BGYNLOSBKBOJJD-IUCAKERBSA-N 0.000 description 1
- QMGUSPDJTPDFSF-UHFFFAOYSA-N Aldophosphamide Chemical class ClCCN(CCCl)P(=O)(N)OCCC=O QMGUSPDJTPDFSF-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010029748 Angiostat Proteins 0.000 description 1
- AQBUFJBHZGRZRV-UHFFFAOYSA-N Ankinomycin Natural products CC1OC1C1C(C=2OC3=C4C(=O)C5=C(O)C(C6OC(C)C(O)C(C)(C6)N(C)C)=CC=C5C(=O)C4=CC(C)=C3C(=O)C=2)(C)O1 AQBUFJBHZGRZRV-UHFFFAOYSA-N 0.000 description 1
- TYGJUQYJMIOZLZ-VTYVZKAMSA-N Antibiotic BU 2867TA Natural products O=C(N[C@H]1C(=O)N[C@@H](C)/C=C\C(=O)NCC[C@@H](O)C1)[C@@H](NC(=O)/C=C/C=C\CCCCCCC)[C@@H](O)C TYGJUQYJMIOZLZ-VTYVZKAMSA-N 0.000 description 1
- OSEDIRANPWGFRX-BONVTDFDSA-N Antibiotic DOB 41 Natural products O([C@@H](C)c1c2nc3c(c(C(=O)O)ccc3)nc2ccc1)C(=O)[C@@H](OC)CO OSEDIRANPWGFRX-BONVTDFDSA-N 0.000 description 1
- 102100027308 Apoptosis regulator BAX Human genes 0.000 description 1
- 108050006685 Apoptosis regulator BAX Proteins 0.000 description 1
- 102100021986 Apoptosis-stimulating of p53 protein 2 Human genes 0.000 description 1
- 101100397240 Arabidopsis thaliana ISPD gene Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 1
- 241000282672 Ateles sp. Species 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 102100032311 Aurora kinase A Human genes 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 102100035683 Axin-2 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- GTHQOPUWLHFKFZ-NNUXYFOWSA-N Baccharin Natural products CC(O)C1OCC(O)C2(C)OC2C(=O)OCC34CCC5(C)OC5C3OC6CC(OC(=O)C=C/C=C/1)C4C6=O GTHQOPUWLHFKFZ-NNUXYFOWSA-N 0.000 description 1
- 101150017888 Bcl2 gene Proteins 0.000 description 1
- 102100026341 Beta-1,4-galactosyltransferase 3 Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 241000157302 Bison bison athabascae Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-BJUDXGSMSA-N Boron-10 Chemical compound [10B] ZOXJGFHDIHLPTG-BJUDXGSMSA-N 0.000 description 1
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 102100025401 Breast cancer type 1 susceptibility protein Human genes 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100034808 CCAAT/enhancer-binding protein alpha Human genes 0.000 description 1
- 108010014064 CCCTC-Binding Factor Proteins 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102100028914 Catenin beta-1 Human genes 0.000 description 1
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 description 1
- 102000038594 Cdh1/Fizzy-related Human genes 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- ZDJRSUWWMAYYID-ZXHXBDCOSA-N Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@]([C@@H](C3=C(O)C=4C(=O)C5=CC=CC(O)=C5C(=O)C=4C(O)=C32)O)(O)CC)CCOCC1 Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@]([C@@H](C3=C(O)C=4C(=O)C5=CC=CC(O)=C5C(=O)C=4C(O)=C32)O)(O)CC)CCOCC1 ZDJRSUWWMAYYID-ZXHXBDCOSA-N 0.000 description 1
- 102100035595 Cohesin subunit SA-2 Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 1
- 108010060313 Core Binding Factor beta Subunit Proteins 0.000 description 1
- 102000008147 Core Binding Factor beta Subunit Human genes 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229930153442 Curcuminoid Natural products 0.000 description 1
- 102000009503 Cyclin-Dependent Kinase Inhibitor p18 Human genes 0.000 description 1
- 108010009367 Cyclin-Dependent Kinase Inhibitor p18 Proteins 0.000 description 1
- 108010016788 Cyclin-Dependent Kinase Inhibitor p21 Proteins 0.000 description 1
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 1
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 1
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 description 1
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102100032218 Cytokine-inducible SH2-containing protein Human genes 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- QWCKQJZIFLGMSD-GSVOUGTGSA-N D-alpha-aminobutyric acid Chemical compound CC[C@@H](N)C(O)=O QWCKQJZIFLGMSD-GSVOUGTGSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100024812 DNA (cytosine-5)-methyltransferase 3A Human genes 0.000 description 1
- 108010024491 DNA Methyltransferase 3A Proteins 0.000 description 1
- 102100035186 DNA excision repair protein ERCC-1 Human genes 0.000 description 1
- 102100035474 DNA polymerase kappa Human genes 0.000 description 1
- 101100226017 Dictyostelium discoideum repD gene Proteins 0.000 description 1
- KYHUYMLIVQFXRI-SJPGYWQQSA-N Didemnin B Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)[C@H](C)O KYHUYMLIVQFXRI-SJPGYWQQSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- MUVMZSPKUBTGDH-UHFFFAOYSA-N Ditrisarubicin B Natural products O1C2CC(=O)C(C)OC2OC(C(C)O2)C1CC2OC(C(C)O1)C(N(C)C)CC1OC1C2=C(O)C(C(=O)C3=CC=CC(O)=C3C3=O)=C3C(O)=C2C(OC2OC(C)C(OC3OC(C)C4OC5OC(C)C(=O)CC5OC4C3)C(C2)N(C)C)CC1(O)CC MUVMZSPKUBTGDH-UHFFFAOYSA-N 0.000 description 1
- 102100029952 Double-strand-break repair protein rad21 homolog Human genes 0.000 description 1
- 241000271571 Dromaius novaehollandiae Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 102100037964 E3 ubiquitin-protein ligase RING2 Human genes 0.000 description 1
- 101150105460 ERCC2 gene Proteins 0.000 description 1
- 102100035079 ETS-related transcription factor Elf-3 Human genes 0.000 description 1
- 102100021717 Early growth response protein 3 Human genes 0.000 description 1
- MGQRRMONVLMKJL-UHFFFAOYSA-N Elsamicin A Natural products O1C(C)C(O)C(OC)C(N)C1OC1C(O)(C)C(O)C(C)OC1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-UHFFFAOYSA-N 0.000 description 1
- 102100036443 Epiplakin Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102100022462 Eukaryotic initiation factor 4A-II Human genes 0.000 description 1
- 102100026353 F-box-like/WD repeat-containing protein TBL1XR1 Human genes 0.000 description 1
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 description 1
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 102100035184 General transcription and DNA repair factor IIH helicase subunit XPD Human genes 0.000 description 1
- 102100033299 Glia-derived nexin Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- JEMVIRAQUIJOCL-UHFFFAOYSA-N Grincamycin Natural products CC1OC(OC2C(CC(OC2C)C=2C(=C3C(=O)C4=C(C5(C(=O)CC(C)(CC5(O)C=C4)OC4OC(C)C(OC5OC(C)C(=O)CC5)CC4)O)C(=O)C3=CC=2)O)O)CCC1OC1CCC(=O)C(C)O1 JEMVIRAQUIJOCL-UHFFFAOYSA-N 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 102100029283 Hepatocyte nuclear factor 3-alpha Human genes 0.000 description 1
- 102100029284 Hepatocyte nuclear factor 3-beta Human genes 0.000 description 1
- 102100030689 Histone H2B type 1-D Human genes 0.000 description 1
- 102100038736 Histone H3.3C Human genes 0.000 description 1
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 1
- 102100027755 Histone-lysine N-methyltransferase 2C Human genes 0.000 description 1
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 1
- 102100039121 Histone-lysine N-methyltransferase MECOM Human genes 0.000 description 1
- 102100029239 Histone-lysine N-methyltransferase, H3 lysine-36 specific Human genes 0.000 description 1
- 102100029433 Homeobox protein Hox-B9 Human genes 0.000 description 1
- 101001097555 Homo sapiens 60S ribosomal protein L22 Proteins 0.000 description 1
- 101000691083 Homo sapiens 60S ribosomal protein L5 Proteins 0.000 description 1
- 101000924266 Homo sapiens AT-rich interactive domain-containing protein 1A Proteins 0.000 description 1
- 101000792947 Homo sapiens AT-rich interactive domain-containing protein 5B Proteins 0.000 description 1
- 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 description 1
- 101000970954 Homo sapiens Activin receptor type-2A Proteins 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000752711 Homo sapiens Apoptosis-stimulating of p53 protein 2 Proteins 0.000 description 1
- 101000798300 Homo sapiens Aurora kinase A Proteins 0.000 description 1
- 101000874569 Homo sapiens Axin-2 Proteins 0.000 description 1
- 101000766180 Homo sapiens Beta-1,4-galactosyltransferase 3 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000945515 Homo sapiens CCAAT/enhancer-binding protein alpha Proteins 0.000 description 1
- 101100329442 Homo sapiens CRIPAK gene Proteins 0.000 description 1
- 101000910338 Homo sapiens Carbonic anhydrase 9 Proteins 0.000 description 1
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 1
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 1
- 101000642968 Homo sapiens Cohesin subunit SA-2 Proteins 0.000 description 1
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 description 1
- 101000943420 Homo sapiens Cytokine-inducible SH2-containing protein Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101000876529 Homo sapiens DNA excision repair protein ERCC-1 Proteins 0.000 description 1
- 101001094659 Homo sapiens DNA polymerase kappa Proteins 0.000 description 1
- 101000865085 Homo sapiens DNA polymerase theta Proteins 0.000 description 1
- 101000584942 Homo sapiens Double-strand-break repair protein rad21 homolog Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 description 1
- 101000877379 Homo sapiens ETS-related transcription factor Elf-3 Proteins 0.000 description 1
- 101000896450 Homo sapiens Early growth response protein 3 Proteins 0.000 description 1
- 101000851943 Homo sapiens Epiplakin Proteins 0.000 description 1
- 101001044475 Homo sapiens Eukaryotic initiation factor 4A-II Proteins 0.000 description 1
- 101000835675 Homo sapiens F-box-like/WD repeat-containing protein TBL1XR1 Proteins 0.000 description 1
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101001062353 Homo sapiens Hepatocyte nuclear factor 3-alpha Proteins 0.000 description 1
- 101001062347 Homo sapiens Hepatocyte nuclear factor 3-beta Proteins 0.000 description 1
- 101001084684 Homo sapiens Histone H2B type 1-D Proteins 0.000 description 1
- 101001031505 Homo sapiens Histone H3.3C Proteins 0.000 description 1
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 1
- 101001008892 Homo sapiens Histone-lysine N-methyltransferase 2C Proteins 0.000 description 1
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 1
- 101000634050 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-36 specific Proteins 0.000 description 1
- 101000989000 Homo sapiens Homeobox protein Hox-B9 Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 1
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 description 1
- 101000717987 Homo sapiens LIM domain-containing protein ajuba Proteins 0.000 description 1
- 101001042362 Homo sapiens Leukemia inhibitory factor receptor Proteins 0.000 description 1
- 101001088887 Homo sapiens Lysine-specific demethylase 5C Proteins 0.000 description 1
- 101001025967 Homo sapiens Lysine-specific demethylase 6A Proteins 0.000 description 1
- 101100076418 Homo sapiens MECOM gene Proteins 0.000 description 1
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 description 1
- 101000831266 Homo sapiens Metalloproteinase inhibitor 4 Proteins 0.000 description 1
- 101000653374 Homo sapiens Methylcytosine dioxygenase TET2 Proteins 0.000 description 1
- 101000582005 Homo sapiens Neuron navigator 3 Proteins 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 101000588303 Homo sapiens Nuclear factor erythroid 2-related factor 3 Proteins 0.000 description 1
- 101000974340 Homo sapiens Nuclear receptor corepressor 1 Proteins 0.000 description 1
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 description 1
- 101000692980 Homo sapiens PHD finger protein 6 Proteins 0.000 description 1
- 101000651906 Homo sapiens Paired amphipathic helix protein Sin3a Proteins 0.000 description 1
- 101001095085 Homo sapiens Periaxin Proteins 0.000 description 1
- 101000619708 Homo sapiens Peroxiredoxin-6 Proteins 0.000 description 1
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 1
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- 101000595751 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 description 1
- 101000735354 Homo sapiens Poly(rC)-binding protein 1 Proteins 0.000 description 1
- 101000728236 Homo sapiens Polycomb group protein ASXL1 Proteins 0.000 description 1
- 101000808592 Homo sapiens Probable ubiquitin carboxyl-terminal hydrolase FAF-X Proteins 0.000 description 1
- 101000945496 Homo sapiens Proliferation marker protein Ki-67 Proteins 0.000 description 1
- 101000601770 Homo sapiens Protein polybromo-1 Proteins 0.000 description 1
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 1
- 101000742859 Homo sapiens Retinoblastoma-associated protein Proteins 0.000 description 1
- 101000703463 Homo sapiens Rho GTPase-activating protein 35 Proteins 0.000 description 1
- 101000654718 Homo sapiens SET-binding protein Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- 101000649929 Homo sapiens Serine/threonine-protein kinase VRK1 Proteins 0.000 description 1
- 101000783404 Homo sapiens Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101000642268 Homo sapiens Speckle-type POZ protein Proteins 0.000 description 1
- 101000707567 Homo sapiens Splicing factor 3B subunit 1 Proteins 0.000 description 1
- 101000808799 Homo sapiens Splicing factor U2AF 35 kDa subunit Proteins 0.000 description 1
- 101000633429 Homo sapiens Structural maintenance of chromosomes protein 1A Proteins 0.000 description 1
- 101000708766 Homo sapiens Structural maintenance of chromosomes protein 3 Proteins 0.000 description 1
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 description 1
- 101000633627 Homo sapiens Teashirt homolog 2 Proteins 0.000 description 1
- 101000633632 Homo sapiens Teashirt homolog 3 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 1
- 101000652324 Homo sapiens Transcription factor SOX-17 Proteins 0.000 description 1
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 description 1
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 description 1
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 description 1
- 101000767597 Homo sapiens Vascular endothelial zinc finger 1 Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 1
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 1
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 1
- 229930185217 Kesarirhodin Natural products 0.000 description 1
- 101100193693 Kirsten murine sarcoma virus K-RAS gene Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AEFLONBTGZFSGQ-VKHMYHEASA-N L-isoglutamine Chemical compound NC(=O)[C@@H](N)CCC(O)=O AEFLONBTGZFSGQ-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 102100026447 LIM domain-containing protein ajuba Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 description 1
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 description 1
- 102100021747 Leukemia inhibitory factor receptor Human genes 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102100033249 Lysine-specific demethylase 5C Human genes 0.000 description 1
- 102100037462 Lysine-specific demethylase 6A Human genes 0.000 description 1
- 108091007767 MALAT1 Proteins 0.000 description 1
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 108700024831 MDS1 and EVI1 Complex Locus Proteins 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000283923 Marmota monax Species 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100024289 Metalloproteinase inhibitor 4 Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102100030803 Methylcytosine dioxygenase TET2 Human genes 0.000 description 1
- 108091034054 MiR-138 Proteins 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 108091062154 Mir-205 Proteins 0.000 description 1
- 108091093189 Mir-375 Proteins 0.000 description 1
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 1
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 1
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 1
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100058550 Mus musculus Bmi1 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- BNQSTAOJRULKNX-UHFFFAOYSA-N N-(6-acetamidohexyl)acetamide Chemical compound CC(=O)NCCCCCCNC(C)=O BNQSTAOJRULKNX-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 108010071382 NF-E2-Related Factor 2 Proteins 0.000 description 1
- WPMGFKKSCCXUAK-YFZUDYRPSA-N Nbeta-acetylstreptothricin D Chemical compound NCCC[C@H](N)CC(=O)NCCC[C@H](N)CC(=O)NCCC[C@H](NC(=O)C)CC(=O)N[C@@H]1[C@H](O)[C@@H](OC(N)=O)[C@@H](CO)O[C@H]1NC1=N[C@@H]2C(=O)NC[C@@H](O)[C@H]2N1 WPMGFKKSCCXUAK-YFZUDYRPSA-N 0.000 description 1
- 229930190254 Neoenactin Natural products 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 102000007530 Neurofibromin 1 Human genes 0.000 description 1
- 108010085793 Neurofibromin 1 Proteins 0.000 description 1
- 102100030464 Neuron navigator 3 Human genes 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical class C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 102000001759 Notch1 Receptor Human genes 0.000 description 1
- 108010029755 Notch1 Receptor Proteins 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- 102100031700 Nuclear factor erythroid 2-related factor 3 Human genes 0.000 description 1
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 1
- 102100022678 Nucleophosmin Human genes 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010031112 Oropharyngeal squamous cell carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 102100026365 PHD finger protein 6 Human genes 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102100027334 Paired amphipathic helix protein Sin3a Human genes 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102100022239 Peroxiredoxin-6 Human genes 0.000 description 1
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 description 1
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 1
- 102100036052 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Human genes 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 102100034960 Poly(rC)-binding protein 1 Human genes 0.000 description 1
- 102100029799 Polycomb group protein ASXL1 Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229930187104 Porothramycin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 102100038603 Probable ubiquitin carboxyl-terminal hydrolase FAF-X Human genes 0.000 description 1
- 102100034836 Proliferation marker protein Ki-67 Human genes 0.000 description 1
- 102100037516 Protein polybromo-1 Human genes 0.000 description 1
- 102100021748 Putative protein CRIPAK Human genes 0.000 description 1
- 108010010225 RA VII Proteins 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 102100038042 Retinoblastoma-associated protein Human genes 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 102100030676 Rho GTPase-activating protein 35 Human genes 0.000 description 1
- JZVJCTVXALSTOA-UHFFFAOYSA-N Rubia akane RA-I Natural products C1=CC(OC)=CC=C1CC(N(C)C(=O)C(CO)NC(=O)C(C)NC(=O)C(N(C1=O)C)C2)C(=O)NC(C)C(=O)N(C)C1CC(C=C1)=CC=C1OC1=CC2=CC=C1O JZVJCTVXALSTOA-UHFFFAOYSA-N 0.000 description 1
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 1
- 102100032741 SET-binding protein Human genes 0.000 description 1
- 241000277331 Salmonidae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- 102100028235 Serine/threonine-protein kinase VRK1 Human genes 0.000 description 1
- 108010005113 Serpin E2 Proteins 0.000 description 1
- JEZZKSQFJNWDCY-UHFFFAOYSA-N Sibanomicin Natural products C1=C2C(=O)N3CC(=CCC)CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-UHFFFAOYSA-N 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- OTABDKFPJQZJRD-UHFFFAOYSA-N Sorangicin A2 Natural products O1C2C=CC=CC=CC(=O)OC(C=C3)C(C(C)=CC(CCCCC(O)=O)C)OC3CC=CCCC=CC(O)C(O)C(O3)CC(O)C(C)C3CC=CC3C(C)C1CC2O3 OTABDKFPJQZJRD-UHFFFAOYSA-N 0.000 description 1
- 102100036422 Speckle-type POZ protein Human genes 0.000 description 1
- 102100031711 Splicing factor 3B subunit 1 Human genes 0.000 description 1
- 102100038501 Splicing factor U2AF 35 kDa subunit Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- 102100029538 Structural maintenance of chromosomes protein 1A Human genes 0.000 description 1
- 102100032723 Structural maintenance of chromosomes protein 3 Human genes 0.000 description 1
- 241000272534 Struthio camelus Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 description 1
- 102100029218 Teashirt homolog 2 Human genes 0.000 description 1
- 102100029222 Teashirt homolog 3 Human genes 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 1
- 102100030243 Transcription factor SOX-17 Human genes 0.000 description 1
- 102100034204 Transcription factor SOX-9 Human genes 0.000 description 1
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 description 1
- 102100027671 Transcriptional repressor CTCF Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004060 Transforming Growth Factor-beta Type II Receptor Human genes 0.000 description 1
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 description 1
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 102100028983 Vascular endothelial zinc finger 1 Human genes 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000282485 Vulpes vulpes Species 0.000 description 1
- 102000040856 WT1 Human genes 0.000 description 1
- 108700020467 WT1 Proteins 0.000 description 1
- 101150084041 WT1 gene Proteins 0.000 description 1
- JAVFSUSPBIUPLW-QEWGJZFKSA-N Withanolide Natural products O=C1[C@@H](C)[C@H](C)C[C@H]([C@@H](C)[C@@H]2[C@@]3(C)[C@H]([C@@H]4[C@@H]([C@]5(C)[C@@H](CC4)CCCC5)CC3)CC2)O1 JAVFSUSPBIUPLW-QEWGJZFKSA-N 0.000 description 1
- 102000056014 X-linked Nuclear Human genes 0.000 description 1
- 108700042462 X-linked Nuclear Proteins 0.000 description 1
- 108010000443 X-ray Repair Cross Complementing Protein 1 Proteins 0.000 description 1
- 102000002258 X-ray Repair Cross Complementing Protein 1 Human genes 0.000 description 1
- 108700031763 Xeroderma Pigmentosum Group D Proteins 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- ZMQRJWIYMXZORG-GZIFKOAOSA-N [(1e,3r,4r,6r,7z,9z,11e)-3,6,13-trihydroxy-3-methyl-1-[(2s)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate Chemical compound OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)(O)=O)[C@@](O)(C)\C=C\[C@@H]1CC=CC(=O)O1 ZMQRJWIYMXZORG-GZIFKOAOSA-N 0.000 description 1
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-N 0.000 description 1
- LJBKHHZPVCABCX-ZYUZMQFOSA-N [(2r,3r,4r,5r)-2,5-dihydroxy-3,4-dimethoxy-6-methylsulfonyloxyhexyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](O)[C@@H](OC)[C@H](OC)[C@H](O)COS(C)(=O)=O LJBKHHZPVCABCX-ZYUZMQFOSA-N 0.000 description 1
- DJUWKQJNJVMFIU-IHAUNJBESA-N [(2r,3r,4s,5r)-3,4,5-triacetyloxy-6-[bis(2-chloroethyl)amino]oxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(N(CCCl)CCCl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O DJUWKQJNJVMFIU-IHAUNJBESA-N 0.000 description 1
- VGAJIIGCSINLBP-IVJDZZAPSA-N [(2r,3s,4s,5r,6r)-6-[(2r,3r,4s,5s,6r)-6-(decanoyloxymethyl)-3,4,5-trihydroxyoxan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl decanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCC)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCC)O1 VGAJIIGCSINLBP-IVJDZZAPSA-N 0.000 description 1
- YJHYHDSHHWKEIS-CJUKMMNNSA-N [(4S,6S,7R,8S)-11-(2-hydroxyethoxy)-7-methoxy-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-dien-8-yl]methyl carbamate Chemical compound CO[C@]12[C@H]3N[C@H]3CN1C1=C([C@H]2COC(N)=O)C(=O)C(OCCO)=C(C)C1=O YJHYHDSHHWKEIS-CJUKMMNNSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- ZUIGQZNTMIGKHP-UHFFFAOYSA-N [1-methyl-5-(methylcarbamoyloxymethyl)-2-methylsulfanylimidazol-4-yl]methyl n-methylcarbamate;hydrochloride Chemical compound Cl.CNC(=O)OCC=1N=C(SC)N(C)C=1COC(=O)NC ZUIGQZNTMIGKHP-UHFFFAOYSA-N 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 1
- MHVFYGIQJNFWGQ-UHFFFAOYSA-N [[4,6-bis[hydroxymethyl(methyl)amino]-1,3,5-triazin-2-yl]-methylamino]methanol Chemical compound OCN(C)C1=NC(N(C)CO)=NC(N(C)CO)=N1 MHVFYGIQJNFWGQ-UHFFFAOYSA-N 0.000 description 1
- JURAJLFHWXNPHG-UHFFFAOYSA-N [acetyl(methylcarbamoyl)amino] n-methylcarbamate Chemical compound CNC(=O)ON(C(C)=O)C(=O)NC JURAJLFHWXNPHG-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229960005339 acitretin Drugs 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000008649 adaptation response Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 239000011795 alpha-carotene Substances 0.000 description 1
- ANVAOWXLWRTKGA-HLLMEWEMSA-N alpha-carotene Natural products C(=C\C=C\C=C(/C=C/C=C(\C=C\C=1C(C)(C)CCCC=1C)/C)\C)(\C=C\C=C(/C=C/[C@H]1C(C)=CCCC1(C)C)\C)/C ANVAOWXLWRTKGA-HLLMEWEMSA-N 0.000 description 1
- 235000003903 alpha-carotene Nutrition 0.000 description 1
- QVBOOBQEGOUUGN-RCBQFDQVSA-N alstonine Chemical compound C1=C[CH]C2=NC3=C(C[C@@H]4C(C(=O)OC)=CO[C@@H](C)[C@@H]4C4)[N+]4=CC=C3C2=C1 QVBOOBQEGOUUGN-RCBQFDQVSA-N 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229950001003 anaxirone Drugs 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 108010005272 antineoplaston A2 Proteins 0.000 description 1
- 108010005286 antineoplaston A3 Proteins 0.000 description 1
- 108010005569 antineoplaston A5 Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- IOASYARYEYRREA-LQAJYKIKSA-N aphidicolin glycinate Chemical compound C1[C@]23[C@]4(C)CC[C@H](O)[C@](C)(CO)[C@H]4CC[C@@H]3C[C@@H]1[C@@](COC(=O)CN)(O)CC2 IOASYARYEYRREA-LQAJYKIKSA-N 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- TXJPJZWNYUQWCP-UHFFFAOYSA-N avarol Natural products CC1CCC2(C)C(=CCCC2(C)C1(C)Cc3cc(O)ccc3O)C TXJPJZWNYUQWCP-UHFFFAOYSA-N 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- DGBITFNXKQHKLI-WXCPUVJDSA-N baccharin Chemical compound C([C@@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1[C@@H]5O[C@]5(C)CC[C@@]13COC(=O)[C@H]1O[C@@]1(C)[C@@H](O)CO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 DGBITFNXKQHKLI-WXCPUVJDSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229950006062 benzotript Drugs 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- OTBHHUPVCYLGQO-UHFFFAOYSA-N bis(3-aminopropyl)amine Chemical compound NCCCNCCCN OTBHHUPVCYLGQO-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 108010014245 bisucaberin Proteins 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- ZNDJOCJUBZZAMN-USYHLRJESA-N bmy-25067 Chemical compound C([C@@H]1N[C@@H]1[C@@]1([C@@H]2COC(N)=O)OC)N1C(C(C=1C)=O)=C2C(=O)C=1NCCSSC1=CC=C([N+]([O-])=O)C=C1 ZNDJOCJUBZZAMN-USYHLRJESA-N 0.000 description 1
- JSKFWUPVIZYJMR-UDOAKELVSA-N bmy-27557 Chemical compound O=C1N(CCN(CC)CC)C(=O)C(C2=C3[CH]C=CC(Cl)=C3NC2=C23)=C1C2=C1C=CC=C(Cl)[C]1N3[C@@H]1O[C@H](CO)[C@@H](OC)[C@H](O)[C@H]1O JSKFWUPVIZYJMR-UDOAKELVSA-N 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- 229950002361 budotitane Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229950009338 caracemide Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 241001233037 catfish Species 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003793 centrosome Anatomy 0.000 description 1
- ORJRBJIJTSDUCG-UHFFFAOYSA-N cervinomycin a2 Chemical compound C1C2(C)OCCN2C(=O)C2=C(O)C3=C(C(=O)C4=C(OC=5C=C(C(=CC=5C4=O)OC)OC)C4=O)C4=CC=C3C=C21 ORJRBJIJTSDUCG-UHFFFAOYSA-N 0.000 description 1
- JZVJCTVXALSTOA-XMPIZRASSA-N chembl1288988 Chemical compound C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](CO)NC(=O)[C@@H](C)NC(=O)[C@@H](N(C1=O)C)C2)C(=O)N[C@@H](C)C(=O)N(C)[C@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O JZVJCTVXALSTOA-XMPIZRASSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229950005158 clanfenur Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 208000037966 cold tumor Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- SBRXTSOCZITGQG-UHFFFAOYSA-N crisnatol Chemical compound C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 SBRXTSOCZITGQG-UHFFFAOYSA-N 0.000 description 1
- 229950007258 crisnatol Drugs 0.000 description 1
- BVQPGVHVDXIPJF-UHFFFAOYSA-L cyclohexane-1,2-diamine;hydron;2-[(2-phosphonatoacetyl)amino]butanedioate;platinum(2+) Chemical compound [H+].[H+].[Pt+2].NC1CCCCC1N.[O-]C(=O)CC(C([O-])=O)NC(=O)CP([O-])([O-])=O BVQPGVHVDXIPJF-UHFFFAOYSA-L 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- KYHUYMLIVQFXRI-UHFFFAOYSA-N didemnin B Natural products CC1OC(=O)C(CC=2C=CC(OC)=CC=2)N(C)C(=O)C2CCCN2C(=O)C(CC(C)C)NC(=O)C(C)C(=O)C(C(C)C)OC(=O)CC(O)C(C(C)CC)NC(=O)C1NC(=O)C(CC(C)C)N(C)C(=O)C1CCCN1C(=O)C(C)O KYHUYMLIVQFXRI-UHFFFAOYSA-N 0.000 description 1
- 108010061297 didemnins Proteins 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- PFWDHRASWSUTIA-KAFJHEIMSA-L disodium;(2s)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoate;2-phenylacetate Chemical compound [Na+].[Na+].[O-]C(=O)CC1=CC=CC=C1.NC(=O)CC[C@@H](C([O-])=O)NC(=O)CC1=CC=CC=C1 PFWDHRASWSUTIA-KAFJHEIMSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- OSEDIRANPWGFRX-UHFFFAOYSA-N dob-41 Chemical compound C1=CC=C2N=C3C(C(C)OC(=O)C(CO)OC)=CC=CC3=NC2=C1C(O)=O OSEDIRANPWGFRX-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 229950003860 elmustine Drugs 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- SIHZWGODIRRSRA-ONEGZZNKSA-N erbstatin Chemical compound OC1=CC=C(O)C(\C=C\NC=O)=C1 SIHZWGODIRRSRA-ONEGZZNKSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- LJQQFQHBKUKHIS-KSFFZXMPSA-N esperamicin A1 Chemical compound O1C[C@H](NC(C)C)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](O)[C@H](NO[C@@H]2O[C@H](C)[C@@H](SC)[C@@H](O)C2)[C@@H](C)O[C@H]1O[C@H]1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O)[C@@H](OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)[C@@]2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-KSFFZXMPSA-N 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- HYSIJEPDMLSIQJ-UHFFFAOYSA-N ethanolate;1-phenylbutane-1,3-dione;titanium(4+) Chemical compound [Ti+4].CC[O-].CC[O-].CC(=O)[CH-]C(=O)C1=CC=CC=C1.CC(=O)[CH-]C(=O)C1=CC=CC=C1 HYSIJEPDMLSIQJ-UHFFFAOYSA-N 0.000 description 1
- GLFJQXMGTAJTGY-AVBZIYQWSA-N ethyl (2s,5s)-5-[[(2s)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-6-[3-[bis(2-chloroethyl)amino]phenyl]-2-(2-methylsulfanylethyl)-4-oxohexanoate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)C[C@@H](CCSC)C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(F)=CC=1)C1=CC=CC(N(CCCl)CCCl)=C1 GLFJQXMGTAJTGY-AVBZIYQWSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960002199 etretinate Drugs 0.000 description 1
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 1
- 229950005096 fazarabine Drugs 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229950010404 fostriecin Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 108091008053 gene clusters Proteins 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- QKMXESBAFIKRAD-LPHDITAFSA-N genkwadaphnin Chemical compound O([C@@H]1[C@H]([C@@]23[C@H]4[C@](C(C(C)=C4)=O)(O)[C@H](O)[C@@]4(CO)O[C@H]4[C@H]3[C@H]3O[C@](O2)(O[C@]31C(C)=C)C=1C=CC=CC=1)C)C(=O)C1=CC=CC=C1 QKMXESBAFIKRAD-LPHDITAFSA-N 0.000 description 1
- QKMXESBAFIKRAD-UHFFFAOYSA-N genkwadaphnin Natural products CC(=C)C12OC(O3)(C=4C=CC=CC=4)OC1C1C4OC4(CO)C(O)C(C(C(C)=C4)=O)(O)C4C31C(C)C2OC(=O)C1=CC=CC=C1 QKMXESBAFIKRAD-UHFFFAOYSA-N 0.000 description 1
- 229930189446 glidobactin Natural products 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 239000000321 herbal drug Substances 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 210000003026 hypopharynx Anatomy 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229930190064 illudin Natural products 0.000 description 1
- 229950006905 ilmofosine Drugs 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000024312 invasive carcinoma Diseases 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 108010002060 leukoregulin Proteins 0.000 description 1
- 108700020781 liblomycin Proteins 0.000 description 1
- 229960005535 lidamycin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 235000020667 long-chain omega-3 fatty acid Nutrition 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229950000547 mafosfamide Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 1
- 229950002676 menogaril Drugs 0.000 description 1
- DZVCFNFOPIZQKX-LTHRDKTGSA-M merocyanine Chemical class [Na+].O=C1N(CCCC)C(=O)N(CCCC)C(=O)C1=C\C=C\C=C/1N(CCCS([O-])(=O)=O)C2=CC=CC=C2O\1 DZVCFNFOPIZQKX-LTHRDKTGSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- AZVARJHZBXHUSO-DZQVEHCYSA-N methyl (1R,4R,12S)-4-methyl-3,7-dioxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),8-diene-4-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-DZQVEHCYSA-N 0.000 description 1
- BOGFADYROAVVTF-MZHQLVBMSA-N methyl (2r,8s)-8-(chloromethyl)-4-hydroxy-2-methyl-1-oxo-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@@H](CCl)C=4C5=C(C(=CC=43)O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 BOGFADYROAVVTF-MZHQLVBMSA-N 0.000 description 1
- FUVBPRRZRLYXHG-XGIZJYENSA-N methyl (2r,8s)-8-chloro-4-hydroxy-7-methyl-1-oxo-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-3,7,8,9-tetrahydro-2h-pyrrolo[3,2-f]quinoline-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C(C)[C@@H](Cl)CC=4C5=C(C(=CC=43)O)N[C@H](C5=O)C(=O)OC)=CC2=C1 FUVBPRRZRLYXHG-XGIZJYENSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 108091044988 miR-125a stem-loop Proteins 0.000 description 1
- 108091049513 miR-125a-1 stem-loop Proteins 0.000 description 1
- 108091040046 miR-125a-2 stem-loop Proteins 0.000 description 1
- 108091030496 miR-138 stem-loop Proteins 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 108010087673 minactivin Proteins 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- BFRVNBMAWXNICS-UHFFFAOYSA-N mitoquidone Chemical compound C1=CC=C2C(=O)C3=CN(CC=4C(=CC=CC=4)C4)C4=C3C(=O)C2=C1 BFRVNBMAWXNICS-UHFFFAOYSA-N 0.000 description 1
- 229950007466 mitoquidone Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- IYIYMCASGKQOCZ-DJRRULDNSA-N motretinide Chemical compound CCNC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C IYIYMCASGKQOCZ-DJRRULDNSA-N 0.000 description 1
- 229960005406 motretinide Drugs 0.000 description 1
- PAVKBQLPQCDVNI-UHFFFAOYSA-N n',n'-diethyl-n-(9-methoxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-1-yl)propane-1,3-diamine Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2C PAVKBQLPQCDVNI-UHFFFAOYSA-N 0.000 description 1
- ZJVAVRRLTFVZIP-UHFFFAOYSA-N n-(2-bromoethyl)-3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound ClCCN1CCCOP1(=O)NCCBr ZJVAVRRLTFVZIP-UHFFFAOYSA-N 0.000 description 1
- QEIMBUYAZCMEGX-UHFFFAOYSA-N n-(2-chloroethyldiazenyl)-n-methylacetamide Chemical compound CC(=O)N(C)N=NCCCl QEIMBUYAZCMEGX-UHFFFAOYSA-N 0.000 description 1
- OQGRFQCUGLKSAV-JTQLQIEISA-N n-[(3s)-2,6-dioxopiperidin-3-yl]-2-phenylacetamide Chemical compound N([C@@H]1C(NC(=O)CC1)=O)C(=O)CC1=CC=CC=C1 OQGRFQCUGLKSAV-JTQLQIEISA-N 0.000 description 1
- SRLPZQAEBMZCIJ-UHFFFAOYSA-N n-[(4-chlorophenyl)carbamoyl]-2-(dimethylamino)-6-fluorobenzamide Chemical compound CN(C)C1=CC=CC(F)=C1C(=O)NC(=O)NC1=CC=C(Cl)C=C1 SRLPZQAEBMZCIJ-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- XEFNBUBDJCJOGM-OUJCMCIWSA-N n-[1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]hexadecanamide Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 XEFNBUBDJCJOGM-OUJCMCIWSA-N 0.000 description 1
- FODMSVBVCPOQRL-UHFFFAOYSA-N n-[2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide;hydrochloride Chemical compound [Cl-].NC(N)=NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCC[NH3+] FODMSVBVCPOQRL-UHFFFAOYSA-N 0.000 description 1
- BLSOATWWAGIRGE-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide;hydrochloride Chemical compound Cl.C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C BLSOATWWAGIRGE-UHFFFAOYSA-N 0.000 description 1
- WKXWMGOTZJGIIK-UHFFFAOYSA-N n-[[4-(5-bromopyrimidin-2-yl)oxy-3-chlorophenyl]carbamoyl]-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)NC(=O)NC(C=C1Cl)=CC=C1OC1=NC=C(Br)C=N1 WKXWMGOTZJGIIK-UHFFFAOYSA-N 0.000 description 1
- AUWFXUHWMBMPTI-UHFFFAOYSA-N n-pyrazin-2-ylnitrous amide Chemical compound O=NNC1=CN=CC=N1 AUWFXUHWMBMPTI-UHFFFAOYSA-N 0.000 description 1
- 229950011492 nafazatrom Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 108010035945 nucleolar organizer region associated proteins Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YVPOTNAPPSUMJX-UHFFFAOYSA-N octadecanoic acid;phosphoric acid Chemical compound OP(O)(O)=O.CCCCCCCCCCCCCCCCCC(O)=O YVPOTNAPPSUMJX-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 208000022698 oropharynx squamous cell carcinoma Diseases 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 210000003695 paranasal sinus Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- LPHSYQSMAGVYNT-UHFFFAOYSA-N pazelliptine Chemical compound N1C2=CC=NC=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2 LPHSYQSMAGVYNT-UHFFFAOYSA-N 0.000 description 1
- 229950006361 pazelliptine Drugs 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 230000009120 phenotypic response Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- FGNPPWFDUWSHQL-UPEPMZDMSA-N pilatin Chemical compound O=CC1=C[C@]2(O)[C@H](OC(=O)/C=C/CCC)C(C)(C)C[C@@H]2[C@]23C(=O)O[C@H](O)[C@@]21C3 FGNPPWFDUWSHQL-UPEPMZDMSA-N 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 229950001030 piritrexim Drugs 0.000 description 1
- KDRKQBMPDQDAJW-UHFFFAOYSA-N piroxantrone Chemical compound OCCNCCN1NC2=C3C(=O)C=CC(=O)C3=C(O)C3=C2C1=CC=C3NCCCN KDRKQBMPDQDAJW-UHFFFAOYSA-N 0.000 description 1
- 229950001746 piroxantrone Drugs 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003857 proglumide Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000002661 proton therapy Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ONQBBCUWASUJGE-UHFFFAOYSA-N putrebactin Natural products ON1CCCCNC(=O)CCC(=O)N(O)CCCCNC(=O)CCC1=O ONQBBCUWASUJGE-UHFFFAOYSA-N 0.000 description 1
- BOGFADYROAVVTF-UHFFFAOYSA-N pyrindamycin A Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3CC(CCl)C=4C5=C(C(=CC=43)O)NC(C5=O)(C)C(=O)OC)=CC2=C1 BOGFADYROAVVTF-UHFFFAOYSA-N 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 108010026350 restrictin-P Proteins 0.000 description 1
- 229950002225 retelliptine Drugs 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- RQHZAASWYUEYCJ-JVWHUAOPSA-N siwenmycin Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-JVWHUAOPSA-N 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- OTABDKFPJQZJRD-QLGZCQHWSA-N sorangicin a Chemical compound C([C@@H]1O[C@H]([C@@H](OC(=O)/C=C\C=C/C=C/[C@H]2O3)C=C1)C(/C)=C/[C@@H](CCCCC(O)=O)C)\C=C\CC\C=C\[C@H](O)[C@H](O)[C@H](O1)C[C@H](O)[C@@H](C)[C@H]1C\C=C\[C@H]1[C@H](C)[C@H]3C[C@H]2O1 OTABDKFPJQZJRD-QLGZCQHWSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229950009641 sparsomycin Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- MFIWRSIQAIKKEY-DSQGJUKISA-N spatol Chemical compound O([C@H]1[C@H]2O[C@@H]2C(=C)[C@H]2[C@H]3[C@H]4[C@@H]([C@]3([C@H](O)C2)C)CC[C@H]4C)C1(C)C MFIWRSIQAIKKEY-DSQGJUKISA-N 0.000 description 1
- MFIWRSIQAIKKEY-UHFFFAOYSA-N spatol Natural products CC1CCC(C2(C(O)C3)C)C1C2C3C(=C)C1OC1C1OC1(C)C MFIWRSIQAIKKEY-UHFFFAOYSA-N 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 229950006050 spiromustine Drugs 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- LLWMPGSQZXZZAE-UHFFFAOYSA-N stypoldione Natural products C1C(C(C(=O)C=C2C)=O)=C2OC21C1(C)CCC3C(C)(C)C(O)CCC3(C)C1CCC2C LLWMPGSQZXZZAE-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- SRXBXVZOQNUGMC-UBOCCBBCSA-N sun-0237 Chemical compound O[C@@H]([C@]1(C)[C@@H]23)C(=O)C=C(C)[C@@H]1C[C@@H]1[C@@]43CO[C@@]2(O)[C@H](O)C(=C)[C@@H]4[C@@H](OC(=O)/C=C/CCCCCCCC)C(=O)O1 SRXBXVZOQNUGMC-UBOCCBBCSA-N 0.000 description 1
- XOCICDFNNMOAKJ-OLGFVZGESA-N sun-2071 Chemical compound O[C@@H]([C@]1(C)[C@@H]23)C(=O)C=C(C)[C@@H]1C[C@@H]1[C@@]43CO[C@@]2(O)[C@H](O)C(=C)[C@@H]4[C@@H](OC(=O)/C=C(C)/CCCCC)C(=O)O1 XOCICDFNNMOAKJ-OLGFVZGESA-N 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 229950002687 talisomycin Drugs 0.000 description 1
- 108010021891 tallimustine Proteins 0.000 description 1
- 229950010168 tauromustine Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- ISTOHHFNKVUOKP-BRUMOIPRSA-N terpentecin Chemical compound O=CC(=O)[C@@]1([C@H](O)C[C@@]2(C)[C@H]3[C@](C(=CCC3)C)(C)C(=O)[C@H](O)[C@H]2C)CO1 ISTOHHFNKVUOKP-BRUMOIPRSA-N 0.000 description 1
- ISTOHHFNKVUOKP-UHFFFAOYSA-N terpentecin Natural products CC1C(O)C(=O)C(C(=CCC2)C)(C)C2C1(C)CC(O)C1(C(=O)C=O)CO1 ISTOHHFNKVUOKP-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-UHFFFAOYSA-N thaliblastine Natural products CN1CCC2=CC(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC2=C(CC3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-UHFFFAOYSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-KYJUHHDHSA-N thalicarpine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC2=C(C[C@H]3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-KYJUHHDHSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229930003802 tocotrienol Natural products 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- IQDSXWRQCKDBMW-NSFJATOBSA-N vintriptol Chemical compound C([C@@H](C[C@@](O)(CC)C1)C[C@@]2(C3=C(OC)C=C4N(C)[C@H]5[C@@]([C@@H]([C@]6(CC)C=CCN7CC[C@]5([C@H]67)C4=C3)O)(O)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)OCC)C(=O)OC)N1CCC1=C2NC2=CC=CC=C12 IQDSXWRQCKDBMW-NSFJATOBSA-N 0.000 description 1
- 229950003415 vintriptol Drugs 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
Definitions
- cancer therapies generally involve multiple treatment modalities, which may include cytotoxic drugs, more targeted therapeutics, biologics, and immunotherapeutics. Although many cancers initially respond dramatically to these drugs, in a majority of cases the evolutionary pro-survival mechanisms of these cancers create adaptive responses that circumvent the mechanism of action of these drugs. This leads to drug resistance and/or recurrence with no real survival benefit to patients.
- a single-agent drug that can effectively address multiple molecular events in a tumor is virtually impossible given that there are many biochemical species that contribute to the disease phenotype and thus different molecular targets require a diversity of drug molecules in order to modulate the biochemical response. Therefore, in the treatment of many diseases, particularly in cases of cancer, it is fairly common to have a cocktail of drugs wherein different drug molecules work through different mechanisms and on different targets. However, one of the most common problems associated with such cocktails is that the number of unique molecules in the cocktail is limited to a handful because interactions among these molecules often lead to undesirable, adverse effects. The second concern is that the molecules in the “artificially” combined drug cocktail often lack true synergy in its pharmacological activity in order to provide a durable clinical response, free from resistance to drugs and/or prevention of recurrence.
- bioactive compounds that comprise the compositions disclosed herein are, in certain embodiments, the metabolites (e.g., the isolated metabolites) produced by plants under intense selection, both for targeting selectivity and high potency through millions of years of evolution.
- compositions comprising: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of peptides, polysaccharides, and proteins; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
- the disclosure relates to pharmaceutical compositions comprising: (a) one or more fractions isolated from Curcuma longa , wherein the fractions comprise one or more extracts of the Curcuma longa enriched with (i) one or more high polarity compounds selected from the group consisting of peptides, polysaccharides, and proteins; (ii) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (iii) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; and (b) one or more pharmaceutical excipients (e.g., one or more of the pharmaceutical excipients described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein).
- pharmaceutical excipients e.g., one or more of the pharmaceutical excipients described in U
- the one or more high polarity extracts comprise between about 5-60% w/w (e.g., 20-60% w/w) of the composition or between about 10-40% w/w (e.g., 25-40% w/w) of the composition.
- the one or more medium polarity extracts comprise between about 20-95% w/w (e.g., 26-95% w/w) of the composition or between about 50-80% w/w (e.g., 50-70% w/w) of the composition.
- the one or more non-polar extracts comprise between about 5-50% w/w of the composition or between about 5-15% w/w of the composition.
- the one or more high polarity extracts are obtained by extracting the botanical material using a solvent system that has a dielectric constant less than 25 or a relative polarity greater than about 0.6.
- the one or more high polarity extracts comprise polysaccharides, peptides, and proteins (e.g., polysaccharides, peptides, and proteins isolated or extracted from Curcuma longa ).
- the one or more medium polarity extracts are obtained by extracting the botanical material using a solvent system that has a dielectric constant between 5 and 25 or a relative polarity between about 0.25-0.6.
- the one or more medium polarity extracts comprise curcumin, demethoxycurcumin, and bisdemethoxycurcumin.
- the one or more low polarity or non-polar extracts are obtained by extracting the botanical material using the solvent system that has dielectric constant less than 5 or a relative polarity less than about 0.25.
- the one or more non-polar extract comprises terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone.
- the composition is formulated for oral administration, buccal administration, sublingual administration and/or transdermal administration to a subject.
- one or more pharmaceutical excipients are selected from the group consisting of diluents, disintegrants, carriers (e.g., hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyether, cyclodextrin, and fatty acid derivatives), plasticizers, gelling agents, water, release agents, flavorings, sweeteners, preservatives, and mixtures thereof.
- one or more pharmaceutical excipients are selected from the group consisting of glycerin, gelatin, water, saline, dextrose, glycerol, ethanol, and combinations thereof.
- the compositions disclosed herein are formulated as a soft pastille, as described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein.
- the pharmaceutical excipients comprise a carrier (e.g., a fish oil carrier).
- one or more of the high polarity extracts, medium polarity extracts, and non-polar extracts are micronized.
- the Curcuma longa extracts do not comprise one or more of insoluble natural polymers such as cellulose and lignin materials.
- the composition comprises about 11-15% w/w (e.g., 11% w/w) of the high polarity polysaccharides, about 41-44% w/w (e.g., 44% w/w) of the medium polarity compound curcumin, and about 3-4% w/w (e.g., 4% w/w) of the non-polar compound ar-tumerone.
- the composition comprises a ratio of about [3]:[6]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively.
- the composition comprises a ratio of about [1]:[1]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively.
- the composition further comprises an effective amount of one or more chemotherapeutic agents.
- chemotherapeutic agents include, but are not limited to, antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- the composition is administered in combination with an immunotherapy agent.
- an immunotherapy agent selected from the group consisting of checkpoint inhibitors, checkpoint blockers, vaccines and CAR-T cells.
- the disclosure relates to methods of treating cancer or a pre-cancerous condition (e.g., leukoplakia), the method comprising administering an effective amount of the composition as described herein to a subject in need thereof, thereby treating cancer or pre-cancerous condition.
- cancer is oral squamous cell carcinoma.
- the pre-cancerous condition is leukoplakia.
- the subject is a mammal (e.g., a human).
- an effective amount of the composition comprises at least about 200-600 mg per day.
- the composition is administered to the subject (e.g., a human subject) at least once daily, at least twice daily, at least three times daily, or at least four times daily.
- the disclosure relates to methods of treating oral or oropharyngeal squamous cell carcinoma in a subject in need thereof, such methods comprising a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more fractions isolated from Curcuma longa , wherein the fractions comprise one or more extracts of the Curcuma longa enriched with (i) one or more high polarity compounds selected from the group consisting of proteins, polysaccharides, and peptides; (ii) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, bisdemethoxycurcumin and combinations thereof; and (iii) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, ⁇ -turmerone and combinations thereof; and (b) one or more pharmaceutical excipients.
- the composition comprises: (a) one or more fractions isolated from Curcuma longa
- the disclosure relates to methods of treating oral squamous cell carcinoma in a subject in need thereof, such methods comprising a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
- the disclosure relates to methods of treating or preventing a pre-cancerous condition in a subject in need thereof.
- the methods and compositions disclosed herein may be used therapeutically or prophylactically to treat or prevent a pre-cancerous condition.
- Such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
- the pre-cancerous condition is leukoplakia.
- the one or more high polarity extracts comprise between about 20-60% w/w of the composition or between about 25-40% w/w of the composition. In some embodiments of the foregoing methods, the one or more medium polarity extracts comprise between about 25-80% w/w of the composition or between about 50-70% w/w of the composition. In some embodiments of the foregoing methods, the one or more non-polar extracts comprise between about 5-50% w/w of the composition or between about 5-15% w/w of the composition.
- Also disclosed herein are methods of promoting or increasing T-cell infiltration in a tumor of a subject e.g., converting a tumor from “cold” to “hot”) thereby improving or increasing the sensitivity of such tumor to, for example, chemotherapy and/or immunotherapy.
- such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight, and thereby promoting or increasing the infiltration of T-cells in the tumor or tumor microenvironment.
- the composition comprises: (a) one or more high polarity
- the one or more high polarity extracts are obtained by isolating or extracting the botanical material using a solvent system that has a dielectric constant less than 25 or have a relative polarity greater than about 0.6.
- the one or more high polarity extracts comprise polysaccharides, and nitrogen containing compounds (e.g., peptides and proteins).
- one or more medium polarity extracts are obtained by isolating or extracting the botanical material using a solvent system that has a dielectric constant between 5 and 25 or have a relative polarity between about 0.25-0.6.
- the one or more medium polarity extracts comprise curcumin, demethoxycurcumin, and bisdemethoxycurcumin.
- one or more low polarity or non-polar extracts are obtained by isolating or extracting the botanical material using a solvent system that has dielectric constant less than 5 or have a relative polarity less than about 0.25.
- the one or more non-polar extracts comprise terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone.
- the composition is formulated for oral administration, buccal administration, sublingual administration or transdermal administration to a subject.
- the one or more pharmaceuticals excipient are selected from the group consisting of diluents, disintegrants, carriers (e.g., hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyether, cyclodextrin, and fatty acid derivatives), plasticizers, gelling agents, water, release agents, flavorings, sweeteners, preservatives, and mixtures thereof.
- one or more pharmaceutical excipients are selected from the group consisting of glycerin, gelatin, water, saline, dextrose, glycerol, ethanol, and combinations thereof.
- the pharmaceutical excipient comprises a carrier (e.g., a fish oil).
- one or more of the high polarity compounds, medium polarity compounds and non-polar compounds are micronized.
- the Curcuma longa extracts do not comprise one or more of insoluble natural polymers, such as cellulose and lignin materials.
- the composition comprises about 11-15% w/w (e.g., 15% w/w) of high polarity polysaccharides, about 41-44% w/w (e.g., 41% w/w) of medium polarity compound curcumin, and about 3-4% w/w (e.g., 3% w/w) of the non-polar compound ar-tumerone.
- the composition comprises a ratio of about [3]:[6]:[1] by weight of the high polarity compounds, medium polarity compounds and non-polar compounds.
- the composition comprises a ratio of about [1]:[1]:[1] by weight of the high polarity compounds, medium polarity compounds and non-polar compounds.
- the composition further comprises an effective amount of one or more chemotherapeutic agents.
- chemotherapeutic agents include, but are not limited to, antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- the composition is administered in combination with an immunotherapy agent.
- an immunotherapy agent selected from the group consisting of checkpoint inhibitors, checkpoint blockers, vaccines and CAR-T cells.
- the high polarity compounds are extracted from the Curcuma longa using a solvent having a dielectric constant greater than about 25 (e.g., formamide, dimethylformamide (DMF), dimethylacetamide (DMAC), methanol, ethanol, water, acetonitrile, and combinations thereof).
- the medium polarity compounds are extracted from the Curcuma longa using a solvent having a dielectric constant between about 5-25 (e.g., ethyl acetate, acetone, 1,2-dichloroethane, THF, isopropyl alcohol, pyridine, ethyl 1,2 dimethylethane, chlorobenzene, and combinations thereof).
- the non-polar compounds are extracted from the Curcuma longa using a solvent having a dielectric constant less than about 5 (e.g., carbon disulfide, carbon tetrachloride, supercritical CO 2 , cyclohexane, diethyl ether, trichloroethylene, O-xylene, and combinations thereof).
- a solvent having a dielectric constant less than about 5 e.g., carbon disulfide, carbon tetrachloride, supercritical CO 2 , cyclohexane, diethyl ether, trichloroethylene, O-xylene, and combinations thereof.
- FIG. 1 depicts a schematic of a process for developing a drug from a plant source.
- the schematic demonstrates the isolation and purification of an active molecule from a plant source and the use of that active molecule in forming a single agent drug (e.g., a silver bullet).
- FIG. 2 depicts a schematic of a second process for developing a drug from a plant source.
- the schematic demonstrates the use of solvent extraction to obtain a variable mixture of molecules from a plant source and the use of that mixture to form an herbal drug active pharmaceutical ingredient (API) (e.g., a simple extract or tincture-based drug).
- API herbal drug active pharmaceutical ingredient
- the resultant drug will consist of multiple molecules, but the relative ratios of the molecules will be dependent on and limited by the extraction process used.
- FIG. 3 illustrates a schematic of a third process for developing a drug from a plant source.
- the schematic demonstrates fractionation processes to create rich fractions of the molecules present based on their physicochemical properties.
- the biological activities of the rich extracts are tested separately and in combination for the phenotypic response that is relevant for the disease of interest as well as the modulation of genes and proteins whose functions are believed to impact the diseases. Based on these results, the ratios of different extracts rich in different classes of molecules are adjusted in relation to each other to achieve the optimum pharmacological effect for a pharmaceutical drug substance (e.g., relationally designed botanical drug).
- a pharmaceutical drug substance e.g., relationally designed botanical drug
- composition AV1016 a high polarity extract, a medium polarity extract and a low polarity extract were combined in a 3:6:1 ratio by weight, respectively, using mechanical blending process.
- a high polarity extract, a medium polarity extract and a low polarity extract were combined in a 1:1:1 ratio by weight, respectively, using mechanical blending process.
- FIG. 4 depicts a graph of varying levels of relative protein expressions observed in CCL-23 cells when exposed to two different ratios of High Polarity, Medium Polarity, and Low Polarity extracts of Curcuma longa.
- FIG. 5 provides a graph of CCL-23 cell killing potency of three different ratios of High Polarity, Medium Polarity, Low Polarity extracts. The number above each bar graph indicates the concentration of curcumin that results in similar observed 50% death of CCL-23 cells (IC 50 ) in all three samples tested.
- FIG. 6 provides a graph of apoptosis achieved through NF-kb modulation of three different formulations of High (HP), Medium (MP), and Low (LP) polarity extracts.
- the numbers above the bars are the concentration of curcumin present in each formulation.
- the compositions identified as AGA215 and AV1016 require less curcumin to achieve the same degree (50%) of cell death.
- the panel on the right shows the relative amounts of HP, MP, and LP in each of the formulations tested.
- the graph shows that the same level of phenotypic effect (cell death) can be achieved by reducing the levels of a particular polyphenol and it is believed that other polyphenols present in medium polarity extract contribute to apoptosis mediated cell death.
- FIG. 7 depicts a graph that shows that relative to the individual extracts rich in Medium Polarity (MP), High Polarity (HP) and Low Polarity (LP) Compounds, two combinations of extracts—AV1016 and AV2017—show higher down-regulation indicating synergistic pharmacological response.
- MP Medium Polarity
- HP High Polarity
- LP Low Polarity
- FIG. 8 represents a graph that demonstrates that, compared to individual extracts rich in Medium Polarity (MP), High Polarity (HP) and Low Polarity (LP) compounds, two combinations of extracts—AV1016 and AV2017—show higher up-regulation indicating synergistic pharmacological response.
- MP Medium Polarity
- HP High Polarity
- LP Low Polarity
- FIG. 9 provides a graph showing an isobologram indicating strong synergy between medium polarity (MP) and low polarity (LP) extracts.
- MP medium polarity
- LP low polarity
- FIG. 10 demonstrates potential mechanisms of action of a composition (AV1016).
- the modulation of key nodes in the tumor progression signaling networks is shown on the left side of the figure.
- Early studies indicate a beneficial role for the compositions in improving oral microbiome in addition to managing tumor stem cell growth.
- Efficacy evidence showing the effect of AV1016 on OSCC cells in vitro is provided on the right side of the figure.
- Networks affected by AV1016 in OSCC include inflammation, proliferation and metastasis, cell cycle control, and apoptosis.
- FIG. 11 demonstrates that the composition AV1016 promotes apoptosis and senescence. Relative protein expression levels are shown upon treatment of CCL-23 cells with 30 mg/mL of AV1016 compared to untreated cells using Western blotting. The data in the provided graphs indicate the impact of AV1016 on the key molecular descriptors of OSCC (e.g., p53, NF ⁇ B, Bcl2).
- OSCC key molecular descriptors of OSCC
- FIG. 12 shows an immunofluorescence (IF) analysis of biopsy samples taken from a patient pre- and post-treatment with AV1016.
- the pre-AV1016 IF slide (left panel) shows scattered CD8 positive cells on the pre-AV1016 tumor biopsy.
- the post-AV1016 tumor biopsy (right panel) showed markedly increased CD8 and CD4 T cells and many of these cells are PD-1 positive.
- There is also PD-L1 expression on tumor cells (red) which was not present on the pre-AV1016 biopsy. This indicates that PD-L1 was expressed in response to T cell infiltration into the tumor microenvironment.
- AV1016 600 mg total dose was delivered to the oral cavity of Patient A using a hydrogel carrier.
- compositions and related methods of use or manufacture of poly-pharmaceutical drugs that consist of combinations of different physical extracts of Curcuma longa .
- the inventions disclosed herein concern a two-step process of preparing the compositions disclosed herein.
- the first step the selective enrichment and/or depletion of various classes of compounds present in C. longa using various methods of extraction takes place.
- These extraction processes are based on the use of solvent systems of varying polarity, as further described herein.
- a low or non-polar extract is obtained by extracting the botanical material (e.g., Curcuma longa ) using a solvent system that has a dielectric constant less than about 5 or relative polarity of less than about 0.2.
- a medium polarity extract is obtained by extracting the botanical material (e.g., Curcuma longa ) using a solvent system that has a dielectric constant between about 5 and 25 and/or a relative polarity equal to or between about 0.25 and 0.6.
- a high polarity extract is obtained using a solvent system that has a dielectric constant greater than about 25 and/or a relative polarity greater than about 0.6
- these extracts are combined to create an optimized formulation based on in-vitro and/or in-vivo evaluations, thereby creating an artificial ratio of the compounds that is unique relative to the ratios of such compounds that are observed in the natural plant.
- the reformulation results in improved pharmacological activity, pharmacokinetic (PK) activity and/or improved pharmacodynamic (PD) activity of such compounds.
- the objective of creating a new polypharmaceutical composition, where multiple molecules act synergistically is to provide a superior pharmacological response.
- the inventions disclosed herein also describe the use of the polypharmaceutical drugs for the treatment of cancer (e.g., oral squamous cell cancer (OSCC)) or pre-cancerous conditions (e.g., leukoplakia), including the use of biomarkers to gauge the efficacy of the therapy.
- cancer e.g., oral squamous cell cancer (OSCC)
- pre-cancerous conditions e.g., leukoplakia
- biomarkers e.g., leukoplakia
- the methods and compositions disclosed herein are useful for the treatment or prevention of oral cancers (e.g., OSCC).
- the methods and compositions disclosed herein are useful for the treatment or prevention of pre-cancerous conditions, such as leukoplakia.
- inventions disclosed herein also describe formulations for targeted and controlled delivery of the polypharmaceutical drugs, in particular, into the local oral cavity and into the systemic circulation of a subject via mucosal absorption (e.g., such inventions may be formulated as a pastille as described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein).
- compositions described herein comprise a combination of extracts containing low or non-polar compounds, medium polarity compounds, and highly polar compounds.
- a “solvent system” refers to either a single solvent or a combination of solvents.
- a “low polarity” or “non-polar” compound refers to the compound(s) extracted using a solvent system having a dielectric constant of less than about 5 and the relative polarity value of less than about 0.2.
- Exemplary low polarity or non-polar compounds may be selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, ⁇ -turmerone, and combinations thereof.
- a “medium polarity” compound refers to the compound(s) being extracted using a solvent system having a dielectric constant between about 5 to 25 and having the relative polarity value between about 0.25 and 0.6.
- Exemplary medium polarity compounds may be selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin, and combinations thereof.
- a “highly polar” or “high polarity” compound refers to the compound(s) extracted using a solvent system that has a dielectric constant greater than about 25 and the relative polarity of greater than about 0.6.
- Exemplary high polarity compounds may be selected from the group consisting of proteins, polysaccharides, peptides, and combinations thereof (e.g., proteins, polysaccharides, peptides isolated from Curcuma longa ). Additional examples of non-polar or low polarity compounds, medium polarity compounds, and high polarity compounds are described by Li et al., Chemical Composition and Product Quality Control of Turmeric ( Curcuma longa ), Pharmaceutical Crops, 2011, 2:28-54, the entire contents of which are incorporated herein by reference.
- the high polarity compounds of the pharmaceutical composition may comprise between about 5% to 60% w/w of the composition, 5% to 50% w/w of the composition, or alternatively 10% to 40% w/w of the composition.
- the medium polarity compounds of the pharmaceutical composition may comprise between about 20% to 95% w/w of the composition, 30% to 80% w/w of the composition, or alternatively 50% to 80% w/w of the composition.
- the non-polar compounds of the pharmaceutical composition may comprise between about 5% to 50% w/w of the composition, 5% to 40% of the composition, or alternatively 5% to 15% w/w of the composition.
- a pharmaceutical composition comprises about 30% w/w of the composition high polarity compounds, about 61% w/w of the composition medium polarity compounds, and about 9% w/w of the composition non-polar compounds. In other aspects, a pharmaceutical composition comprises about 33% w/w of the composition high polarity compounds, about 33% w/w of the composition medium polarity compounds, and about 33% w/w of the composition non-polar compounds.
- compositions disclosed herein comprise a ratio of about [3]:[6]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively. In some embodiments, the compositions disclosed herein comprise a ratio of about [1]:[1]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively.
- the composition comprises a combination of extracts containing low or non-polar compounds in the range of about 3% to 100% w/w of the composition (e.g., about 10% w/w), medium polarity compounds in the range of about 3% to 95% w/w of the composition (e.g., about 60% w/w), and highly polar compounds in the range of about 3% to 55% w/w of the composition (e.g., about 30% w/w).
- low or non-polar compounds in the range of about 3% to 100% w/w of the composition (e.g., about 10% w/w), medium polarity compounds in the range of about 3% to 95% w/w of the composition (e.g., about 60% w/w), and highly polar compounds in the range of about 3% to 55% w/w of the composition (e.g., about 30% w/w).
- the composition comprises a combination of extracts containing low or non-polar compounds in the range of about 4% to 50% w/w of the composition (e.g., about 33% w/w), medium polarity compounds in the range of about 5% to 60% w/w of the composition (e.g., about 33% w/w), and highly polar compounds in the range of about 10% to 40% w/w of the composition (e.g., about 33% w/w).
- One or more high polarity compounds may be extracted using a solvent system that has a relative polarity greater than about 0.6.
- one or more medium polarity compounds may be extracted using a solvent system that has a relative polarity between about 0.25 and 0.6.
- One or more non-polar or low polarity compounds may be extracted using a solvent system that has a relative polarity of less than about 0.25.
- “relative polarity” refers to the values for relative polarity normalized from measurements of solvent shifts of absorption spectra and are described in Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry , Wiley-VCH Publishers, 3 rd ed., 2003, the contents of which are incorporated herein by reference.
- the pharmaceutical composition disclosed herein may comprise a ratio of high polarity compounds, medium polarity compounds, and non-polar compounds.
- the pharmaceutical composition comprises a [3]:[6]:[1] ratio of high polarity compounds, medium polarity compounds, and non-polar compounds.
- the pharmaceutical composition comprises a [1]:[1]:[1] ratio of high polarity compounds, medium polarity compounds, and non-polar compounds.
- the pharmaceutical compositions disclosed herein comprise one or more fractions isolated from Curcuma longa (e.g., one, two, three, four, five, six or more fractions).
- the fractions may comprise one or more extracts of the C. longa enriched with one or more high polarity compounds, one or more medium polarity compounds, and one or more non-polar compounds.
- the C. longa extracts do not comprise one or more of water-insoluble natural polymers, such as lignin and cellulose.
- the high polarity compounds are extracted from the C. longa using a solvent having a dielectric constant greater than about 25.
- the solvent having a dielectric constant greater than about 25 may be selected from the group consisting of formamide, dimethylformamide (DMF), dimethylacetamide (DMAC), methanol, ethanol, water, acetonitrile, and combinations thereof.
- the solvent having a dielectric constant greater than about 25 is water.
- the medium polarity compounds are extracted from the C. longa using a solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6.
- the solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6 may be selected from the group consisting of ethyl acetate, acetone, 1,2-dichloroethane, THF, isopropyl alcohol, pyridine, ethyl benzoate, 1,2-dimethoxyethane, chlorobenzene, and combinations thereof.
- the solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6 is ethyl acetate.
- the non-polar or low polarity compounds are extracted from the C. longa using a solvent having a dielectric constant less than about 5 or relative polarity value of less than about 0.2.
- the solvent having a dielectric constant less than about 5 may be selected from the group consisting of carbon disulfide, carbon tetrachloride, supercritical CO 2 , cyclohexane, diethyl ether, trichloroethylene, O-xylene, and combinations thereof.
- the solvent having a dielectric constant less than about 5 or relative polarity value of less than about 0.2 is CO 2 .
- High polarity compounds may be selected from the group consisting of proteins, polysaccharides (e.g., hydrolyzable polysaccharides), and peptides.
- Medium polarity compounds may be selected from the group consisting of polyphenols, such as curcumin, demethoxycurcumin, bisdemethoxycurcumin and combinations thereof.
- Non-polar or low polarity compounds may be selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, ⁇ -turmerone and combinations thereof.
- one or more of the high polarity compounds, medium polarity compounds, and non-polar compounds are micronized.
- the pharmaceutical composition may further include one or more pharmaceutical excipients.
- the pharmaceutical excipient may be selected from the group consisting of plasticizer, gelling agent, water, release agent, flavoring, sweetener, preservative, diluents, disintegrants, carriers (e.g., a hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyethers, cyclodextrin, fatty acid derivatives), and mixtures thereof.
- Suitable excipients may include, for example, glycerin, gelatin, water, saline, dextrose, glycerol, ethanol or the like, and combinations thereof.
- the compositions disclosed herein may comprise one or more of the pharmaceutical excipients disclosed in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein.
- the pharmaceutical compositions described herein demonstrate improved pharmacologic, pharmacokinetic (PK) and/or improved pharmacodynamic (PD) properties relative to a naturally occurring Curcuma longa .
- the PK value is influenced by the delivery method of the pharmaceutical composition.
- the pharmaceutical compositions described herein demonstrate improved efficacy relative to naturally occurring Curcuma longa . It is generally understood that the various polar compounds of the pharmaceutical composition demonstrate synergy, thereby contributing to the benefits identified.
- cancer is oral cancer (e.g., oral squamous cell carcinoma).
- cancer is oral cancer is Glioblastoma, lung cancer, colon cancer and pancreatic cancer.
- the condition is pre-cancerous (e.g., a pre-cancerous condition, such as leukoplakia) where the methods and compositions disclosed herein may be used therapeutically and/or prophylactically.
- compositions disclosed herein are useful for promoting and/or increasing T-cell infiltration in a tumor of a subject.
- such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, ⁇ -turmerone, and ⁇ -turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight, and thereby promoting or increasing the infiltration of T-cells in the tumor or tumor microenvironment of a subject.
- the composition comprises: (a) one or more
- a “subject” means a human or animal (e.g., a primate). Usually, the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
- Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
- Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
- the subject is a mammal, e.g., a primate, e.g., a human.
- the subject is a mammal.
- the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples.
- the methods described herein can be used to treat domesticated animals and/or pets.
- a subject can be male or female.
- a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications related to such a condition, and optionally, but need not have already undergone treatment for a condition or one or more complications related to the condition.
- a subject can also be one who has not been previously diagnosed as having a condition in need of treatment or one or more complications related to such a condition. Rather, a subject can include one who exhibits one or more risk factors for a condition or one or more complications related to a condition.
- a “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at increased risk of developing that condition relative to a given reference population.
- An effective amount of the pharmaceutical composition administered to a subject comprises at least about 100-600 mg per day, and in some aspects at least about 200-500 mg per day of the active extracts or ingredients. This amount comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds.
- the pharmaceutical composition comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds in a 3:6:1 ratio.
- the pharmaceutical composition comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds in a 1:1:1 ratio.
- the pharmaceutical composition is administered to the subject (e.g., administered buccally or sublingually) at least one, at least two, at least three, at least four, at least five times daily or more. In some aspects 100 mg of the pharmaceutical composition is administered to a subject one, two, three, four, or five times daily. In certain aspects 100 mg of the high, medium and low polarity compound (e.g., at 3:6:1 ratio, respectively) is administered to a subject twice a day.
- the high, medium and low polarity compound e.g., at 3:6:1 ratio, respectively
- a method of treating cancer e.g., oral squamous cell carcinoma
- the method comprises a step of administering a pharmaceutical composition to the subject, wherein the composition comprises (a) one or more fractions isolated from Curcuma longa , wherein the fractions comprise one or more extracts of the C.
- the pharmaceutical composition is formulated for administration to a subject (e.g., oral, buccal, transdermal or sublingual administration).
- Pharmaceutical compositions comprise one or more agents or compositions that have therapeutic utility, and a pharmaceutically acceptable carrier (e.g., a carrier that facilitates delivery of agents or compositions).
- Agents and pharmaceutical compositions disclosed herein may be administered by any suitable means such as orally, intranasally, subcutaneously, intramuscularly, intravenously, intra-arterially, parenterally, intraperitoneally, intrathecally, intratracheally, ocularly, sublingually, vaginally, rectally, dermally, or as an aerosol.
- compounds and composition of the invention may, for example, be inhaled, ingested or administered by systemic routes.
- administration modes or routes, are available. The particular mode selected will typically depend on factors such as the particular compound selected, the particular condition being treated and the dosage required for therapeutic efficacy.
- the methods described herein, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces acceptable levels of efficacy without causing clinically unacceptable adverse effects.
- Exemplary methods for administering the pharmaceutical composition to the subject include oral, buccal, sublingual and/or transdermal administration.
- compositions described herein may be delivered to a subject by means of a pharmaceutically acceptable carrier (e.g., a fish oil carrier).
- a pharmaceutically acceptable carrier e.g., a fish oil carrier
- Such carriers are well known in the art and can be one or more compatible solid or liquid vehicles, fillers, diluents, or encapsulating substances which are suitable for administration to a human or non-human animal.
- a pharmaceutically acceptable carrier is a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.
- the term “compatible,” as used herein, means that the components of the pharmaceutical compositions are capable of being comingled with an agent, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations.
- Pharmaceutically acceptable carriers should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or non-human animal being treated.
- substances which can serve as pharmaceutically acceptable carriers are pyrogen-free water; isotonic saline; phosphate buffer solutions; sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, powdered tragacanth, malt; gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, oil of theobroma , fish oil such as those containing long-chain omega-3 polyunsaturated fatty acids (PUFA), polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol, sugar, alginic acid, cocoa butter (suppository base), emulsifiers such as the Tweens as well as other non-chain
- wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. It will be appreciated that a pharmaceutical composition can contain multiple different pharmaceutically acceptable carriers.
- compositions can include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials which are well-known in the art.
- pharmaceutically acceptable carrier to be used in conjunction with the compounds of the present invention takes into consideration the way the compound is to be administered to the subject.
- Such preparations may routinely contain one or more salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
- the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof in certain embodiments.
- Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
- pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. It will also be understood that a compound can be provided as a pharmaceutically acceptable pro-drug, or an active metabolite can be used.
- the pharmaceutical composition may be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
- the pharmaceutical composition may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections, and usual ways for oral, parenteral or surgical administration.
- the invention also embraces pharmaceutical compositions which are formulated for local administration, such as by implants.
- the pharmaceutical composition is formulated for administration as a pastille. Examples include those described by U.S. Pat. No. 9,913,873, incorporated herein by reference.
- compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active agent.
- Other compositions include suspensions in aqueous liquids or non-aqueous liquids, such as syrups, elixirs and/or emulsions.
- the pharmaceutical composition is administered in combination with one or more therapies.
- Therapies may be selected from the group consisting of immunotherapy, chemotherapy, radiotherapy, proton therapy, surgery, and combinations thereof.
- the composition may be administered before, during, or after administration of a therapy.
- the composition is administered in combination with one or more chemotherapeutic agents.
- the pharmaceutical compositions described herein may further include one or more chemotherapeutic agents.
- the chemotherapeutic agent may be an antineoplastic agent.
- the antineoplastic agents are selected from the group consisting of antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- Suitable antimetabolite agents may be selected from the group consisting of 5-FU-fibrinogen, acanthfolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrell Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.
- EX-015 benzrabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, and ur
- Suitable alkylating-type agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17
- Antibiotic-type agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-
- Additional agents may be selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlors
- a checkpoint inhibitor is selected from the group consisting of a CTLA4 blockade (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab, Pembrolizumab, and antibody BGB-A317), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, and duralumab), an intrinsic checkpoint blockage (e.g., CISH), and combinations thereof.
- a CTLA4 blockade e.g., ipilimumab
- a PD-1 inhibitor e.g., Nivolumab, Pembrolizumab, and antibody BGB-A317
- a PD-L1 inhibitor e.g., atezolizumab, avelumab, and duralumab
- an intrinsic checkpoint blockage e.g., CISH
- the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated otherwise. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
- the invention includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum.
- Numerical values include values expressed as percentages. For any embodiment of the invention in which a numerical value is prefaced by “about” or “approximately”, the invention includes an embodiment in which the exact value is recited. For any embodiment of the invention in which a numerical value is not prefaced by “about” or “approximately”, the invention includes an embodiment in which the value is prefaced by “about” or “approximately”.
- HNSCC head and neck squamous cell carcinoma
- Oral squamous cell carcinoma is one such cancer where this molecular heterogeneity poses serious challenges to drug designers who traditionally tend to focus on one or a handful of targets that they seek to inhibit or activate.
- OSCC Oral squamous cell carcinoma
- these targets often continue to mutate and establish alternative signaling pathways in the tumor when a particular pathway is blocked.
- a single-agent drug that can effectively address multiple molecular events in a tumor is virtually impossible given that there is enormous diversity of the binding sites of the targets. Therefore, in treatment of many diseases, particularly in case of cancer, it is fairly common to have a cocktail of drugs wherein different drug molecules work through different mechanisms and on different targets, for example, one or more of those targets identified in FIG. 10 and/or in Table 2, below.
- the compositions disclosed herein modulate one or more of the targets identified in Table 2.
- one of the most common problems associated with such cocktails is that the number of unique molecules in a cocktail is limited to a handful because interactions among these molecules often lead to unwarranted effects.
- a second issue is that the molecules in the drug cocktail lack true synergy that can overcome the resistance or recurrence mechanisms and produce a durable clinical response.
- a polypharmaceutical drug containing multiple molecules that are capable of pleiotropic and truly synergistic action to address vast molecular heterogeneity of the tumor and the tumor microenvironment.
- Plant-derived drugs used in traditional systems of medicine are naturally occurring polypharmaceuticals.
- the bioactive molecules in such drugs which are usually the metabolites produced by the plants, are the result of millions of years of evolution.
- Nature has explored chemical-diversity space extensively with a vast array of organic/biological scaffolds and through combinatorial biology and under evolutionary selection pressure has produced a chemical library unmatched by any combinatorial library produced by humans.
- structural scaffolds on which many related compounds are based have been under intense selection, both for targeting selectivity and high potency for many millions of years.
- Plant-derived bioactive molecules generally can be broken down into various classes such as polyphenols, terpenes, alkaloids, sugars, peptides, and large molecules, including proteins and polysaccharides. Many of the molecules have been studied extensively for their medicinal properties. In the case of polyphenols, for example, the following four molecules have been extensively tested for their anti-cancer properties.
- Taxol which is a terpenoid.
- a traditional approach for designing a polypharmaceutical drug is the use of a “crude” plant extract as shown in FIG. 2 . While such a therapeutic drug consists of multiple molecules, the composition of the extracts, as well as the relative ratios, are dependent on and limited by the extraction process used. Such a composition is not optimized for a disease of interest and often lacks sufficient potency.
- the gene clusters responsible for production of different classes of metabolites generally tend to code for a biosynthetic pathway that produces the molecules belonging to the same class bearing structural similarity. These “co-evolved” molecules are intended to work together functionally. Additionally, different classes of molecules further tend to synergize where each class of molecule is designed to play a distinct role ranging from its versatility in binding to the proteins of interest, to avoidance of the toxicity, to enabling the absorption of the pharmacologically active molecules. While a botanical source produces these compounds in a range of ratios relative to each other, the naturally occurring ratios is not optimized for a human disease of interest, particularly so for a molecularly heterogeneous cancer such as OSCC.
- the present inventors fractionated the molecules present in a botanical source using the processes that create rich fractions based on their physico-chemical properties. The present inventors then tested the biological activity of the rich fractions separately and in combination to optimize the relative ratios of the active compounds.
- the inventive subject matter comprises the development of a polypharmaceutical drug that primarily uses fractions comprising rich extracts of Curcuma longa , a perennial herb grown in many parts of the world, but in a unique ratio (i.e., different than that found in nature) optimized for treating human diseases.
- C. longa and more particularly, curcumin one polyphenolic metabolite from C. longa , is extensively studied for its medicinal properties. While curcumin is often used as a proxy for overall pharmacological properties of C. longa , it is only one of over 200 small bioactive molecules found in C. longa .
- an inventive composition is developed where major classes of molecules from C. longa are combined to create polypharmaceutical compositions.
- the polypharmaceutical compositions comprise a combination of extracts containing low or non-polar compounds, medium polarity compounds, and highly polar compounds in a variety of ratios.
- a low or non-polar extract of C. longa is created by extracting the dried, powdered rhizome with a solvent system that has a dielectric constant less than 5 or a relative polarity of less than 0.2.
- This extract is rich in a class of compounds known as terpenoids and its concentration is no less than 50% by weight.
- the extract is usually characterized by the presence and levels of a signature compound Ar-Turmerone.
- An extract rich in medium polarity molecules is obtained by extracting C. longa using a solvent system that has a dielectric constant between 5 and 25 or a relative polarity is equal to or between 0.25 and 0.6.
- Such an extract is generally rich in a class of compounds known as polyphenols whose concentration ranges from at least 90% curcuminoid and is usually characterized by a signature compound Curcumin.
- polyphenols are described by Li et al., Chemical Composition and Product Quality Control of Turmeric ( Curcuma longa L.), Pharmaceutical Crops, 2011, 2:28-54, the entire contents of which incorporated herein by reference.
- An extract rich in high polarity molecules is obtained by extracting C. longa using a solvent system that has a dielectric constant greater than 25 or a relative polarity greater than 0.6.
- Such an extract is usually rich in nitrogen-containing compounds and polysaccharides whose concentration ranges from 2.5%-15% and at least 25% respectively.
- Table 1 summarizes the ratios of the yields of the extracts obtained relative to the weight of the processed starting materials. Approximately only 5% of the desired components are obtained for each type of extract from the raw plant material used.
- Phenotypic changes induced by the specific compositions clearly indicate a specific targeting of a definitive gene pathway for cell killing (apoptosis and autophagic signaling axis).
- the effect of HP, MP, and LP clearly signaled differences in effect on certain genes, with demonstration of synergistic targeting on multiple gene pathways, when combined in some definite proportions.
- HNSCC Head and Neck Squamous Cell Carcinoma
- OSCC Oral squamous cell cancer
- Major risk factors include tobacco and alcohol consumption along with environmental and genetic factors (Brinkman and Wong, Curr Opin Oncol. 18(3):228-33, 2006; Figuerido et al., Drug Discovery Today Disease Mechanisms 1(2):273-281, November 2004).
- These cancers are usually detected at late-stages when the disease has advanced and therefore results in poor prognosis and survival.
- TCGA Cancer Genome Atlas
- compositions disclosed herein modulate or otherwise affect one or more of the pathways listed in Table 2.
- compositions disclosed herein modulate the expression (e.g., increase or decrease the expression) of one or more of the biomarkers listed in Table 2.
- Immunotherapy drugs belonging to a group called checkpoint inhibitors are antibody-based agents that mobilize the immune T-cell response.
- Checkpoint mechanisms such as those based on PD-1 and PD-L1
- the immune system responds by turning the T cell and other macrophages off, allowing cancer cells to multiply.
- Checkpoint inhibitors by various mechanisms, make these cancer cells recognizable and thus, allow the immune system (e.g., T cells), to activate and thus destroy cancer cells.
- checkpoint inhibitors are not necessarily effective for all patients.
- One reason checkpoint inhibitors may be ineffective is that cancerous tumor may have a limited number of T cells to be turned on. Tumors may be termed “hot” when they are filled with T cells and “cold” when they contain only a few T cells.
- the classifying of a tumor as “cold” or “hot” can be referred to as an immunoscore.
- “Hot” tumors are generally more sensitive to immunotherapy due to the increased amount of T cells, and therefore patients with “hot” tumors tend to respond to immunotherapy, such as that based on checkpoint inhibitors, better than patients with “cold” tumors.
- AV1016 acts as a primer of tumors.
- administration of AV1016 to a patient resulted in a tumor changing from “cold” to “hot,” as illustrated in FIG. 12 .
- the patient then returned to the clinic approximately two weeks later for a scheduled surgical procedure.
- AV1016 600 mg dose
- hydrogel carrier a hydrogel carrier
- the patient underwent surgical resection of his tumor (post-AV1016 administration).
- the pre- and post-AV1016 immunofluorescence results illustrated in FIG. 12 evidence that the patient's tumor changed from “cold” to “hot” after administration of AV1016.
- AV1016 demonstrated efficacy as a primer of tumors for use in combination with other immunotherapies.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Botany (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed are compositions and methods for treating or ameliorating the symptoms of cancer (e.g., oral cancer) by using a poly-pharmaceutical drug, whose composition consists of relationally optimized ratios of bioactive compounds to enhance their pharmacological characteristics.
Description
- This application is a continuation of U.S. application Ser. No. 17/044,696, filed Oct. 1, 2020, which is a national stage filing under 35 U.S.C. 371 of International Application No. PCT/US2019/025465, filed Apr. 2, 2019, which claims the benefit of U.S. Provisional Application No. 62/651,683, filed Apr. 2, 2018. The entire teachings of the above applications are incorporated herein by reference. International Application No. PCT/US2019/025465 was published under PCT Article 21(2) in English.
- Presently available cancer therapies generally involve multiple treatment modalities, which may include cytotoxic drugs, more targeted therapeutics, biologics, and immunotherapeutics. Although many cancers initially respond dramatically to these drugs, in a majority of cases the evolutionary pro-survival mechanisms of these cancers create adaptive responses that circumvent the mechanism of action of these drugs. This leads to drug resistance and/or recurrence with no real survival benefit to patients.
- A single-agent drug that can effectively address multiple molecular events in a tumor is virtually impossible given that there are many biochemical species that contribute to the disease phenotype and thus different molecular targets require a diversity of drug molecules in order to modulate the biochemical response. Therefore, in the treatment of many diseases, particularly in cases of cancer, it is fairly common to have a cocktail of drugs wherein different drug molecules work through different mechanisms and on different targets. However, one of the most common problems associated with such cocktails is that the number of unique molecules in the cocktail is limited to a handful because interactions among these molecules often lead to undesirable, adverse effects. The second concern is that the molecules in the “artificially” combined drug cocktail often lack true synergy in its pharmacological activity in order to provide a durable clinical response, free from resistance to drugs and/or prevention of recurrence.
- Needed are new therapeutics, compositions, and methods of making and/or using poly-pharmaceutical drugs containing multiple compounds that are capable of pleiotropic and truly synergistic action to address vast molecular heterogeneity of the tumor and the tumor microenvironment.
- Disclosed herein are therapeutic and pharmaceutical compositions and related methods of use or manufacture of plant-derived poly-pharmaceutical drugs. The bioactive compounds that comprise the compositions disclosed herein are, in certain embodiments, the metabolites (e.g., the isolated metabolites) produced by plants under intense selection, both for targeting selectivity and high potency through millions of years of evolution.
- Nature has produced a chemical library unmatched by any combinatorial library produced by a human. The inventions disclosed herein further recognize that the naturally occurring composition of these poly-pharmaceuticals extracted from the plants requires “re-optimization” to address therapeutic challenges that are unique only to humans, including cancer.
- In certain aspects, disclosed herein are pharmaceutical compositions comprising: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of peptides, polysaccharides, and proteins; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
- In some aspects, the disclosure relates to pharmaceutical compositions comprising: (a) one or more fractions isolated from Curcuma longa, wherein the fractions comprise one or more extracts of the Curcuma longa enriched with (i) one or more high polarity compounds selected from the group consisting of peptides, polysaccharides, and proteins; (ii) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (iii) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; and (b) one or more pharmaceutical excipients (e.g., one or more of the pharmaceutical excipients described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein).
- In some embodiments, the one or more high polarity extracts comprise between about 5-60% w/w (e.g., 20-60% w/w) of the composition or between about 10-40% w/w (e.g., 25-40% w/w) of the composition. In some embodiments, the one or more medium polarity extracts comprise between about 20-95% w/w (e.g., 26-95% w/w) of the composition or between about 50-80% w/w (e.g., 50-70% w/w) of the composition. In some embodiments, the one or more non-polar extracts comprise between about 5-50% w/w of the composition or between about 5-15% w/w of the composition. In some embodiments, the one or more high polarity extracts are obtained by extracting the botanical material using a solvent system that has a dielectric constant less than 25 or a relative polarity greater than about 0.6. In some embodiments, the one or more high polarity extracts comprise polysaccharides, peptides, and proteins (e.g., polysaccharides, peptides, and proteins isolated or extracted from Curcuma longa). In some embodiments, the one or more medium polarity extracts are obtained by extracting the botanical material using a solvent system that has a dielectric constant between 5 and 25 or a relative polarity between about 0.25-0.6. In some embodiments, the one or more medium polarity extracts comprise curcumin, demethoxycurcumin, and bisdemethoxycurcumin. In some embodiments, the one or more low polarity or non-polar extracts are obtained by extracting the botanical material using the solvent system that has dielectric constant less than 5 or a relative polarity less than about 0.25. In some embodiments, the one or more non-polar extract comprises terpenoids, ar-turmerone, α-turmerone, and β-turmerone.
- In some embodiments, the composition is formulated for oral administration, buccal administration, sublingual administration and/or transdermal administration to a subject. In some embodiments, one or more pharmaceutical excipients are selected from the group consisting of diluents, disintegrants, carriers (e.g., hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyether, cyclodextrin, and fatty acid derivatives), plasticizers, gelling agents, water, release agents, flavorings, sweeteners, preservatives, and mixtures thereof. In some embodiments, one or more pharmaceutical excipients are selected from the group consisting of glycerin, gelatin, water, saline, dextrose, glycerol, ethanol, and combinations thereof. In certain aspects, the compositions disclosed herein are formulated as a soft pastille, as described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein. In some embodiments, the pharmaceutical excipients comprise a carrier (e.g., a fish oil carrier).
- In some embodiments, one or more of the high polarity extracts, medium polarity extracts, and non-polar extracts are micronized. In some embodiments, the Curcuma longa extracts do not comprise one or more of insoluble natural polymers such as cellulose and lignin materials.
- In some embodiments, the composition comprises about 11-15% w/w (e.g., 11% w/w) of the high polarity polysaccharides, about 41-44% w/w (e.g., 44% w/w) of the medium polarity compound curcumin, and about 3-4% w/w (e.g., 4% w/w) of the non-polar compound ar-tumerone. In some embodiments, the composition comprises a ratio of about [3]:[6]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively. In some embodiments, the composition comprises a ratio of about [1]:[1]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively.
- In some embodiments, the composition further comprises an effective amount of one or more chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- In certain embodiments of the foregoing methods, the composition is administered in combination with an immunotherapy agent. For example, in certain embodiments, the compositions disclosed herein are administered to a subject in combination with an immunotherapy agent selected from the group consisting of checkpoint inhibitors, checkpoint blockers, vaccines and CAR-T cells.
- In some aspects, the disclosure relates to methods of treating cancer or a pre-cancerous condition (e.g., leukoplakia), the method comprising administering an effective amount of the composition as described herein to a subject in need thereof, thereby treating cancer or pre-cancerous condition. In some embodiments, cancer is oral squamous cell carcinoma. In some embodiments, the pre-cancerous condition is leukoplakia. In some embodiments, the subject is a mammal (e.g., a human).
- In some embodiments, an effective amount of the composition comprises at least about 200-600 mg per day. In some embodiments, the composition is administered to the subject (e.g., a human subject) at least once daily, at least twice daily, at least three times daily, or at least four times daily.
- In some aspects, the disclosure relates to methods of treating oral or oropharyngeal squamous cell carcinoma in a subject in need thereof, such methods comprising a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more fractions isolated from Curcuma longa, wherein the fractions comprise one or more extracts of the Curcuma longa enriched with (i) one or more high polarity compounds selected from the group consisting of proteins, polysaccharides, and peptides; (ii) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, bisdemethoxycurcumin and combinations thereof; and (iii) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, β-turmerone and combinations thereof; and (b) one or more pharmaceutical excipients.
- In certain aspects, the disclosure relates to methods of treating oral squamous cell carcinoma in a subject in need thereof, such methods comprising a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
- In certain aspects, the disclosure relates to methods of treating or preventing a pre-cancerous condition in a subject in need thereof. For example, in certain embodiments, the methods and compositions disclosed herein may be used therapeutically or prophylactically to treat or prevent a pre-cancerous condition. Such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight. In certain aspects, the pre-cancerous condition is leukoplakia.
- In some embodiments of the foregoing methods, the one or more high polarity extracts comprise between about 20-60% w/w of the composition or between about 25-40% w/w of the composition. In some embodiments of the foregoing methods, the one or more medium polarity extracts comprise between about 25-80% w/w of the composition or between about 50-70% w/w of the composition. In some embodiments of the foregoing methods, the one or more non-polar extracts comprise between about 5-50% w/w of the composition or between about 5-15% w/w of the composition.
- Also disclosed herein are methods of promoting or increasing T-cell infiltration in a tumor of a subject (e.g., converting a tumor from “cold” to “hot”) thereby improving or increasing the sensitivity of such tumor to, for example, chemotherapy and/or immunotherapy. In certain aspects, such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight, and thereby promoting or increasing the infiltration of T-cells in the tumor or tumor microenvironment.
- In some embodiments of the foregoing methods, the one or more high polarity extracts are obtained by isolating or extracting the botanical material using a solvent system that has a dielectric constant less than 25 or have a relative polarity greater than about 0.6. In some embodiments, the one or more high polarity extracts comprise polysaccharides, and nitrogen containing compounds (e.g., peptides and proteins). In some embodiments, one or more medium polarity extracts are obtained by isolating or extracting the botanical material using a solvent system that has a dielectric constant between 5 and 25 or have a relative polarity between about 0.25-0.6. In some embodiments, the one or more medium polarity extracts comprise curcumin, demethoxycurcumin, and bisdemethoxycurcumin. In some embodiments, one or more low polarity or non-polar extracts are obtained by isolating or extracting the botanical material using a solvent system that has dielectric constant less than 5 or have a relative polarity less than about 0.25. In some embodiments, the one or more non-polar extracts comprise terpenoids, ar-turmerone, α-turmerone, and β-turmerone.
- In some embodiments of the foregoing methods, the composition is formulated for oral administration, buccal administration, sublingual administration or transdermal administration to a subject. In some embodiments, the one or more pharmaceuticals excipient are selected from the group consisting of diluents, disintegrants, carriers (e.g., hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyether, cyclodextrin, and fatty acid derivatives), plasticizers, gelling agents, water, release agents, flavorings, sweeteners, preservatives, and mixtures thereof. In some embodiments, one or more pharmaceutical excipients are selected from the group consisting of glycerin, gelatin, water, saline, dextrose, glycerol, ethanol, and combinations thereof. In some embodiments, the pharmaceutical excipient comprises a carrier (e.g., a fish oil).
- In some embodiments of the foregoing methods, one or more of the high polarity compounds, medium polarity compounds and non-polar compounds are micronized. In some embodiments, the Curcuma longa extracts do not comprise one or more of insoluble natural polymers, such as cellulose and lignin materials.
- In some embodiment of the foregoing methods, the composition comprises about 11-15% w/w (e.g., 15% w/w) of high polarity polysaccharides, about 41-44% w/w (e.g., 41% w/w) of medium polarity compound curcumin, and about 3-4% w/w (e.g., 3% w/w) of the non-polar compound ar-tumerone. In some embodiments of the foregoing methods, the composition comprises a ratio of about [3]:[6]:[1] by weight of the high polarity compounds, medium polarity compounds and non-polar compounds. In some embodiments of the foregoing methods, the composition comprises a ratio of about [1]:[1]:[1] by weight of the high polarity compounds, medium polarity compounds and non-polar compounds.
- In some embodiments, the composition further comprises an effective amount of one or more chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- In certain embodiments of the foregoing methods, the composition is administered in combination with an immunotherapy agent. For example, in certain embodiments, the compositions disclosed herein are administered to a subject in combination with an immunotherapy agent selected from the group consisting of checkpoint inhibitors, checkpoint blockers, vaccines and CAR-T cells.
- In some embodiments, the high polarity compounds are extracted from the Curcuma longa using a solvent having a dielectric constant greater than about 25 (e.g., formamide, dimethylformamide (DMF), dimethylacetamide (DMAC), methanol, ethanol, water, acetonitrile, and combinations thereof). In some embodiments, the medium polarity compounds are extracted from the Curcuma longa using a solvent having a dielectric constant between about 5-25 (e.g., ethyl acetate, acetone, 1,2-dichloroethane, THF, isopropyl alcohol, pyridine,
ethyl 1,2 dimethylethane, chlorobenzene, and combinations thereof). In some embodiments, the non-polar compounds are extracted from the Curcuma longa using a solvent having a dielectric constant less than about 5 (e.g., carbon disulfide, carbon tetrachloride, supercritical CO2, cyclohexane, diethyl ether, trichloroethylene, O-xylene, and combinations thereof). - The above discussed, and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention when taken in conjunction with the accompanying examples.
- The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.
-
FIG. 1 depicts a schematic of a process for developing a drug from a plant source. The schematic demonstrates the isolation and purification of an active molecule from a plant source and the use of that active molecule in forming a single agent drug (e.g., a silver bullet). -
FIG. 2 depicts a schematic of a second process for developing a drug from a plant source. The schematic demonstrates the use of solvent extraction to obtain a variable mixture of molecules from a plant source and the use of that mixture to form an herbal drug active pharmaceutical ingredient (API) (e.g., a simple extract or tincture-based drug). The resultant drug will consist of multiple molecules, but the relative ratios of the molecules will be dependent on and limited by the extraction process used. -
FIG. 3 illustrates a schematic of a third process for developing a drug from a plant source. The schematic demonstrates fractionation processes to create rich fractions of the molecules present based on their physicochemical properties. The biological activities of the rich extracts are tested separately and in combination for the phenotypic response that is relevant for the disease of interest as well as the modulation of genes and proteins whose functions are believed to impact the diseases. Based on these results, the ratios of different extracts rich in different classes of molecules are adjusted in relation to each other to achieve the optimum pharmacological effect for a pharmaceutical drug substance (e.g., relationally designed botanical drug). For example, to make the composition AV1016, a high polarity extract, a medium polarity extract and a low polarity extract were combined in a 3:6:1 ratio by weight, respectively, using mechanical blending process. In another example, to make the composition AV2017, a high polarity extract, a medium polarity extract and a low polarity extract were combined in a 1:1:1 ratio by weight, respectively, using mechanical blending process. -
FIG. 4 depicts a graph of varying levels of relative protein expressions observed in CCL-23 cells when exposed to two different ratios of High Polarity, Medium Polarity, and Low Polarity extracts of Curcuma longa. -
FIG. 5 provides a graph of CCL-23 cell killing potency of three different ratios of High Polarity, Medium Polarity, Low Polarity extracts. The number above each bar graph indicates the concentration of curcumin that results in similar observed 50% death of CCL-23 cells (IC50) in all three samples tested. -
FIG. 6 provides a graph of apoptosis achieved through NF-kb modulation of three different formulations of High (HP), Medium (MP), and Low (LP) polarity extracts. The numbers above the bars are the concentration of curcumin present in each formulation. The compositions identified as AGA215 and AV1016 require less curcumin to achieve the same degree (50%) of cell death. The panel on the right shows the relative amounts of HP, MP, and LP in each of the formulations tested. The graph shows that the same level of phenotypic effect (cell death) can be achieved by reducing the levels of a particular polyphenol and it is believed that other polyphenols present in medium polarity extract contribute to apoptosis mediated cell death. By going from a single molecule-based approach to a multiple molecule-based approach the effective concentration of the therapeutic agents can be reduced and thus the therapeutic index can be widened. -
FIG. 7 depicts a graph that shows that relative to the individual extracts rich in Medium Polarity (MP), High Polarity (HP) and Low Polarity (LP) Compounds, two combinations of extracts—AV1016 and AV2017—show higher down-regulation indicating synergistic pharmacological response. -
FIG. 8 represents a graph that demonstrates that, compared to individual extracts rich in Medium Polarity (MP), High Polarity (HP) and Low Polarity (LP) compounds, two combinations of extracts—AV1016 and AV2017—show higher up-regulation indicating synergistic pharmacological response. -
FIG. 9 provides a graph showing an isobologram indicating strong synergy between medium polarity (MP) and low polarity (LP) extracts. Each data point represents IC50 of an MP+LP combination that yields equivalent NF-KB mediated apoptosis in vitro. The zone above the Additive line indicates antagonism and the zone below the Additive line indicates synergy. The combinations of extracts AV1016 and AV2017 are in the synergistic region of the isobologram. -
FIG. 10 demonstrates potential mechanisms of action of a composition (AV1016). The modulation of key nodes in the tumor progression signaling networks is shown on the left side of the figure. Early studies indicate a beneficial role for the compositions in improving oral microbiome in addition to managing tumor stem cell growth. Efficacy evidence showing the effect of AV1016 on OSCC cells in vitro is provided on the right side of the figure. Networks affected by AV1016 in OSCC include inflammation, proliferation and metastasis, cell cycle control, and apoptosis. -
FIG. 11 demonstrates that the composition AV1016 promotes apoptosis and senescence. Relative protein expression levels are shown upon treatment of CCL-23 cells with 30 mg/mL of AV1016 compared to untreated cells using Western blotting. The data in the provided graphs indicate the impact of AV1016 on the key molecular descriptors of OSCC (e.g., p53, NFκB, Bcl2). -
FIG. 12 shows an immunofluorescence (IF) analysis of biopsy samples taken from a patient pre- and post-treatment with AV1016. The pre-AV1016 IF slide (left panel) shows scattered CD8 positive cells on the pre-AV1016 tumor biopsy. The post-AV1016 tumor biopsy (right panel) showed markedly increased CD8 and CD4 T cells and many of these cells are PD-1 positive. There is also PD-L1 expression on tumor cells (red) which was not present on the pre-AV1016 biopsy. This indicates that PD-L1 was expressed in response to T cell infiltration into the tumor microenvironment. This may indicate adaptive PD-L1 expression, which further suggests that an immune checkpoint blockade (anti-PD-1 or anti-PD-L1 antibody) may work on this patient after the patient's tumor has been primed by AV1016. AV1016 (600 mg total dose) was delivered to the oral cavity of Patient A using a hydrogel carrier. - Disclosed herein are compositions and related methods of use or manufacture of poly-pharmaceutical drugs that consist of combinations of different physical extracts of Curcuma longa. In certain embodiments, the inventions disclosed herein concern a two-step process of preparing the compositions disclosed herein. In the first step, the selective enrichment and/or depletion of various classes of compounds present in C. longa using various methods of extraction takes place. These extraction processes are based on the use of solvent systems of varying polarity, as further described herein. For example, in certain aspects, a low or non-polar extract is obtained by extracting the botanical material (e.g., Curcuma longa) using a solvent system that has a dielectric constant less than about 5 or relative polarity of less than about 0.2. In some embodiments, a medium polarity extract is obtained by extracting the botanical material (e.g., Curcuma longa) using a solvent system that has a dielectric constant between about 5 and 25 and/or a relative polarity equal to or between about 0.25 and 0.6. In certain embodiments, a high polarity extract is obtained using a solvent system that has a dielectric constant greater than about 25 and/or a relative polarity greater than about 0.6
- In the second step, these extracts are combined to create an optimized formulation based on in-vitro and/or in-vivo evaluations, thereby creating an artificial ratio of the compounds that is unique relative to the ratios of such compounds that are observed in the natural plant. The reformulation results in improved pharmacological activity, pharmacokinetic (PK) activity and/or improved pharmacodynamic (PD) activity of such compounds.
- The objective of creating a new polypharmaceutical composition, where multiple molecules act synergistically is to provide a superior pharmacological response.
- The inventions disclosed herein also describe the use of the polypharmaceutical drugs for the treatment of cancer (e.g., oral squamous cell cancer (OSCC)) or pre-cancerous conditions (e.g., leukoplakia), including the use of biomarkers to gauge the efficacy of the therapy. In certain aspects, the methods and compositions disclosed herein are useful for the treatment or prevention of oral cancers (e.g., OSCC). In certain aspects, the methods and compositions disclosed herein are useful for the treatment or prevention of pre-cancerous conditions, such as leukoplakia. The inventions disclosed herein also describe formulations for targeted and controlled delivery of the polypharmaceutical drugs, in particular, into the local oral cavity and into the systemic circulation of a subject via mucosal absorption (e.g., such inventions may be formulated as a pastille as described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein).
- The pharmaceutical compositions described herein comprise a combination of extracts containing low or non-polar compounds, medium polarity compounds, and highly polar compounds. As used herein, a “solvent system” refers to either a single solvent or a combination of solvents. As used herein, a “low polarity” or “non-polar” compound refers to the compound(s) extracted using a solvent system having a dielectric constant of less than about 5 and the relative polarity value of less than about 0.2. Exemplary low polarity or non-polar compounds may be selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, β-turmerone, and combinations thereof. As used herein, a “medium polarity” compound refers to the compound(s) being extracted using a solvent system having a dielectric constant between about 5 to 25 and having the relative polarity value between about 0.25 and 0.6. Exemplary medium polarity compounds may be selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin, and combinations thereof. As used herein, a “highly polar” or “high polarity” compound refers to the compound(s) extracted using a solvent system that has a dielectric constant greater than about 25 and the relative polarity of greater than about 0.6. Exemplary high polarity compounds may be selected from the group consisting of proteins, polysaccharides, peptides, and combinations thereof (e.g., proteins, polysaccharides, peptides isolated from Curcuma longa). Additional examples of non-polar or low polarity compounds, medium polarity compounds, and high polarity compounds are described by Li et al., Chemical Composition and Product Quality Control of Turmeric (Curcuma longa), Pharmaceutical Crops, 2011, 2:28-54, the entire contents of which are incorporated herein by reference.
- The high polarity compounds of the pharmaceutical composition may comprise between about 5% to 60% w/w of the composition, 5% to 50% w/w of the composition, or alternatively 10% to 40% w/w of the composition. The medium polarity compounds of the pharmaceutical composition may comprise between about 20% to 95% w/w of the composition, 30% to 80% w/w of the composition, or alternatively 50% to 80% w/w of the composition. The non-polar compounds of the pharmaceutical composition may comprise between about 5% to 50% w/w of the composition, 5% to 40% of the composition, or alternatively 5% to 15% w/w of the composition. In some aspects, a pharmaceutical composition comprises about 30% w/w of the composition high polarity compounds, about 61% w/w of the composition medium polarity compounds, and about 9% w/w of the composition non-polar compounds. In other aspects, a pharmaceutical composition comprises about 33% w/w of the composition high polarity compounds, about 33% w/w of the composition medium polarity compounds, and about 33% w/w of the composition non-polar compounds.
- In some embodiments, the compositions disclosed herein comprise a ratio of about [3]:[6]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively. In some embodiments, the compositions disclosed herein comprise a ratio of about [1]:[1]:[1] of high polarity extracts, medium polarity extracts and non-polar extracts, respectively.
- In some aspects, the composition comprises a combination of extracts containing low or non-polar compounds in the range of about 3% to 100% w/w of the composition (e.g., about 10% w/w), medium polarity compounds in the range of about 3% to 95% w/w of the composition (e.g., about 60% w/w), and highly polar compounds in the range of about 3% to 55% w/w of the composition (e.g., about 30% w/w). In certain aspects, the composition comprises a combination of extracts containing low or non-polar compounds in the range of about 4% to 50% w/w of the composition (e.g., about 33% w/w), medium polarity compounds in the range of about 5% to 60% w/w of the composition (e.g., about 33% w/w), and highly polar compounds in the range of about 10% to 40% w/w of the composition (e.g., about 33% w/w).
- One or more high polarity compounds may be extracted using a solvent system that has a relative polarity greater than about 0.6. In some aspects, one or more medium polarity compounds may be extracted using a solvent system that has a relative polarity between about 0.25 and 0.6. One or more non-polar or low polarity compounds may be extracted using a solvent system that has a relative polarity of less than about 0.25. As used herein, “relative polarity” refers to the values for relative polarity normalized from measurements of solvent shifts of absorption spectra and are described in Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003, the contents of which are incorporated herein by reference.
- The pharmaceutical composition disclosed herein may comprise a ratio of high polarity compounds, medium polarity compounds, and non-polar compounds. In some aspects, the pharmaceutical composition comprises a [3]:[6]:[1] ratio of high polarity compounds, medium polarity compounds, and non-polar compounds. In other aspects, the pharmaceutical composition comprises a [1]:[1]:[1] ratio of high polarity compounds, medium polarity compounds, and non-polar compounds.
- In some aspects, the pharmaceutical compositions disclosed herein comprise one or more fractions isolated from Curcuma longa (e.g., one, two, three, four, five, six or more fractions). The fractions may comprise one or more extracts of the C. longa enriched with one or more high polarity compounds, one or more medium polarity compounds, and one or more non-polar compounds. In certain embodiments, the C. longa extracts do not comprise one or more of water-insoluble natural polymers, such as lignin and cellulose.
- In some aspects, the high polarity compounds are extracted from the C. longa using a solvent having a dielectric constant greater than about 25. The solvent having a dielectric constant greater than about 25 may be selected from the group consisting of formamide, dimethylformamide (DMF), dimethylacetamide (DMAC), methanol, ethanol, water, acetonitrile, and combinations thereof. In certain aspects, the solvent having a dielectric constant greater than about 25 is water. In some aspects, the medium polarity compounds are extracted from the C. longa using a solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6. The solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6 may be selected from the group consisting of ethyl acetate, acetone, 1,2-dichloroethane, THF, isopropyl alcohol, pyridine, ethyl benzoate, 1,2-dimethoxyethane, chlorobenzene, and combinations thereof. In certain aspects, the solvent having a dielectric constant between about 5 and 25 or relative polarity value between about 0.25 and 0.6 is ethyl acetate. In some aspects, the non-polar or low polarity compounds are extracted from the C. longa using a solvent having a dielectric constant less than about 5 or relative polarity value of less than about 0.2. The solvent having a dielectric constant less than about 5 may be selected from the group consisting of carbon disulfide, carbon tetrachloride, supercritical CO2, cyclohexane, diethyl ether, trichloroethylene, O-xylene, and combinations thereof. In certain aspects the solvent having a dielectric constant less than about 5 or relative polarity value of less than about 0.2 is CO2.
- High polarity compounds may be selected from the group consisting of proteins, polysaccharides (e.g., hydrolyzable polysaccharides), and peptides. Medium polarity compounds may be selected from the group consisting of polyphenols, such as curcumin, demethoxycurcumin, bisdemethoxycurcumin and combinations thereof. Non-polar or low polarity compounds may be selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, β-turmerone and combinations thereof. In some aspects, one or more of the high polarity compounds, medium polarity compounds, and non-polar compounds are micronized.
- The pharmaceutical composition may further include one or more pharmaceutical excipients. The pharmaceutical excipient may be selected from the group consisting of plasticizer, gelling agent, water, release agent, flavoring, sweetener, preservative, diluents, disintegrants, carriers (e.g., a hydrogel matrix), binders, adhesives, surfactants, lubricants, solvents, permeation enhancers (e.g., menthol, surfactants, alcohols, polyols, polyethers, cyclodextrin, fatty acid derivatives), and mixtures thereof. Suitable excipients may include, for example, glycerin, gelatin, water, saline, dextrose, glycerol, ethanol or the like, and combinations thereof. In certain aspects, the compositions disclosed herein may comprise one or more of the pharmaceutical excipients disclosed in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein.
- The pharmaceutical compositions described herein demonstrate improved pharmacologic, pharmacokinetic (PK) and/or improved pharmacodynamic (PD) properties relative to a naturally occurring Curcuma longa. In some aspects the PK value is influenced by the delivery method of the pharmaceutical composition. Further, the pharmaceutical compositions described herein demonstrate improved efficacy relative to naturally occurring Curcuma longa. It is generally understood that the various polar compounds of the pharmaceutical composition demonstrate synergy, thereby contributing to the benefits identified.
- Also disclosed herein are methods of treating cancer or pre-cancerous conditions in a subject, such methods comprising the administration of the compositions disclosed herein to the subject. In some embodiments, a method of treating cancer or pre-cancerous conditions includes administering to the subject in need thereof an effective amount of the pharmaceutical composition described herein, thereby treating cancer. In some aspects, cancer is oral cancer (e.g., oral squamous cell carcinoma). In some aspects, cancer is oral cancer is Glioblastoma, lung cancer, colon cancer and pancreatic cancer. In some aspects, the condition is pre-cancerous (e.g., a pre-cancerous condition, such as leukoplakia) where the methods and compositions disclosed herein may be used therapeutically and/or prophylactically.
- In certain embodiments, the compositions disclosed herein are useful for promoting and/or increasing T-cell infiltration in a tumor of a subject. For example, disclosed herein are methods of converting a tumor from “cold” to “hot,” thereby improving or increasing the sensitivity of such tumor to, for example, chemotherapy and/or immunotherapy. In certain aspects, such methods comprise a step of administering a pharmaceutical composition to the subject, wherein the composition comprises: (a) one or more high polarity compounds isolated from Curcuma longa and selected from the group consisting of proteins, polysaccharides, and peptides; (b) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight, and thereby promoting or increasing the infiltration of T-cells in the tumor or tumor microenvironment of a subject.
- As used herein, a “subject” means a human or animal (e.g., a primate). Usually, the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents. In certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “patient”, “individual” and “subject” are used interchangeably herein. Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. In addition, the methods described herein can be used to treat domesticated animals and/or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications related to such a condition, and optionally, but need not have already undergone treatment for a condition or one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a condition in need of treatment or one or more complications related to such a condition. Rather, a subject can include one who exhibits one or more risk factors for a condition or one or more complications related to a condition. A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at increased risk of developing that condition relative to a given reference population.
- An effective amount of the pharmaceutical composition administered to a subject comprises at least about 100-600 mg per day, and in some aspects at least about 200-500 mg per day of the active extracts or ingredients. This amount comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds. In some aspects the pharmaceutical composition comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds in a 3:6:1 ratio. In some aspect the pharmaceutical composition comprises the combined mass of the high polarity compounds, the medium polarity compounds, and the low or non-polarity compounds in a 1:1:1 ratio. In some aspects, the pharmaceutical composition is administered to the subject (e.g., administered buccally or sublingually) at least one, at least two, at least three, at least four, at least five times daily or more. In some
aspects 100 mg of the pharmaceutical composition is administered to a subject one, two, three, four, or five times daily. Incertain aspects 100 mg of the high, medium and low polarity compound (e.g., at 3:6:1 ratio, respectively) is administered to a subject twice a day. - In some embodiments, a method of treating cancer (e.g., oral squamous cell carcinoma) in a subject in need thereof is disclosed. The method comprises a step of administering a pharmaceutical composition to the subject, wherein the composition comprises (a) one or more fractions isolated from Curcuma longa, wherein the fractions comprise one or more extracts of the C. longa enriched with (i) one or more high polarity compounds selected from the group consisting of proteins, polysaccharides, and peptides; (ii) one or more medium polarity compounds selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, bisdemethoxycurcumin and combinations thereof; and (iii) one or more non-polar compounds selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, β-turmerone and combinations thereof; and (b) one or more pharmaceutical excipients (e.g., one or more of the pharmaceutical excipients described in U.S. Pat. No. 9,913,873, the entire contents of which are incorporated by reference herein).
- In some embodiments, the pharmaceutical composition is formulated for administration to a subject (e.g., oral, buccal, transdermal or sublingual administration). Pharmaceutical compositions comprise one or more agents or compositions that have therapeutic utility, and a pharmaceutically acceptable carrier (e.g., a carrier that facilitates delivery of agents or compositions). Agents and pharmaceutical compositions disclosed herein may be administered by any suitable means such as orally, intranasally, subcutaneously, intramuscularly, intravenously, intra-arterially, parenterally, intraperitoneally, intrathecally, intratracheally, ocularly, sublingually, vaginally, rectally, dermally, or as an aerosol. Depending upon the type of condition (e.g., cancer) to be treated, compounds and composition of the invention may, for example, be inhaled, ingested or administered by systemic routes. Thus, a variety of administration modes, or routes, are available. The particular mode selected will typically depend on factors such as the particular compound selected, the particular condition being treated and the dosage required for therapeutic efficacy. The methods described herein, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces acceptable levels of efficacy without causing clinically unacceptable adverse effects. Exemplary methods for administering the pharmaceutical composition to the subject include oral, buccal, sublingual and/or transdermal administration.
- The pharmaceutical compositions described herein may be delivered to a subject by means of a pharmaceutically acceptable carrier (e.g., a fish oil carrier). Such carriers are well known in the art and can be one or more compatible solid or liquid vehicles, fillers, diluents, or encapsulating substances which are suitable for administration to a human or non-human animal. In preferred embodiments, a pharmaceutically acceptable carrier is a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. The term “compatible,” as used herein, means that the components of the pharmaceutical compositions are capable of being comingled with an agent, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations. Pharmaceutically acceptable carriers should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or non-human animal being treated.
- Some examples of substances which can serve as pharmaceutically acceptable carriers are pyrogen-free water; isotonic saline; phosphate buffer solutions; sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, powdered tragacanth, malt; gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, oil of theobroma, fish oil such as those containing long-chain omega-3 polyunsaturated fatty acids (PUFA), polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol, sugar, alginic acid, cocoa butter (suppository base), emulsifiers such as the Tweens as well as other non-toxic compatible substances used in pharmaceutical formulation. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. It will be appreciated that a pharmaceutical composition can contain multiple different pharmaceutically acceptable carriers.
- Pharmaceutically acceptable compositions can include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials which are well-known in the art. The choice of pharmaceutically acceptable carrier to be used in conjunction with the compounds of the present invention takes into consideration the way the compound is to be administered to the subject. Such preparations may routinely contain one or more salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof in certain embodiments. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. It will also be understood that a compound can be provided as a pharmaceutically acceptable pro-drug, or an active metabolite can be used.
- The pharmaceutical composition may be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
- The pharmaceutical composition may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections, and usual ways for oral, parenteral or surgical administration. The invention also embraces pharmaceutical compositions which are formulated for local administration, such as by implants. In some aspects the pharmaceutical composition is formulated for administration as a pastille. Examples include those described by U.S. Pat. No. 9,913,873, incorporated herein by reference.
- Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active agent. Other compositions include suspensions in aqueous liquids or non-aqueous liquids, such as syrups, elixirs and/or emulsions.
- In some embodiments, the pharmaceutical composition is administered in combination with one or more therapies. Therapies may be selected from the group consisting of immunotherapy, chemotherapy, radiotherapy, proton therapy, surgery, and combinations thereof. The composition may be administered before, during, or after administration of a therapy. In some aspects, the composition is administered in combination with one or more chemotherapeutic agents. The pharmaceutical compositions described herein may further include one or more chemotherapeutic agents.
- The chemotherapeutic agent may be an antineoplastic agent. In some aspects, the antineoplastic agents are selected from the group consisting of antimetabolite agents, antibiotic-type agents, alkylating agents, hormonal agents, immunological agents, interferon-type agents, matrix metalloproteinases, and superoxide dismutase mimics.
- Suitable antimetabolite agents may be selected from the group consisting of 5-FU-fibrinogen, acanthfolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrell Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, and uricytin.
- Suitable alkylating-type agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin, and trimelamol.
- Antibiotic-type agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and zorubicin.
- Additional agents may be selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, Yamanouchi YM-534, and combinations thereof.
- The pharmaceutical composition may be administered in combination with a checkpoint inhibitor. In some embodiments a checkpoint inhibitor is selected from the group consisting of a CTLA4 blockade (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab, Pembrolizumab, and antibody BGB-A317), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, and duralumab), an intrinsic checkpoint blockage (e.g., CISH), and combinations thereof.
- The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description.
- Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.
- All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or prior publication, or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.
- One skilled in the art readily appreciates that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The details of the description and the examples herein are representative of certain embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Modifications therein and other uses will occur to those skilled in the art. These modifications are encompassed within the spirit of the invention. It will be readily apparent to a person skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.
- The articles “a” and “an” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to include the plural referents. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention provides all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim (or, as relevant, any other claim) unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. It is contemplated that all embodiments described herein are applicable to all different aspects of the invention where appropriate. It is also contemplated that any of the embodiments or aspects can be freely combined with one or more other such embodiments or aspects whenever appropriate. Where elements are presented as lists, e.g., in Markush group or similar format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not in every case been specifically set forth in so many words herein. It should also be understood that any embodiment or aspect of the invention can be explicitly excluded from the claims, regardless of whether the specific exclusion is recited in the specification. For example, any one or more active agents, additives, ingredients, optional agents, types of organism, disorders, subjects, or combinations thereof, can be excluded.
- Where the claims or description relate to a composition of matter, it is to be understood that methods of making or using the composition of matter according to any of the methods disclosed herein, and methods of using the composition of matter for any of the purposes disclosed herein are aspects of the invention, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where the claims or description relate to a method, e.g., it is to be understood that methods of making compositions useful for performing the method, and products produced according to the method, are aspects of the invention, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.
- Where ranges are given herein, the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated otherwise. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is also understood that where a series of numerical values is stated herein, the invention includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum. Numerical values, as used herein, include values expressed as percentages. For any embodiment of the invention in which a numerical value is prefaced by “about” or “approximately”, the invention includes an embodiment in which the exact value is recited. For any embodiment of the invention in which a numerical value is not prefaced by “about” or “approximately”, the invention includes an embodiment in which the value is prefaced by “about” or “approximately”.
- “Approximately” or “about” generally includes numbers that fall within a range of 1% or in some embodiments within a range of 5% of a number or in some embodiments within a range of 10% of a number in either direction (greater than or less than the number) unless otherwise stated or otherwise evident from the context (except where such number would impermissibly exceed 100% of a possible value). It should be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one act, the order of the acts of the method is not necessarily limited to the order in which the acts of the method are recited, but the invention includes embodiments in which the order is so limited. It should also be understood that unless otherwise indicated or evident from the context, any product or composition described herein may be considered “isolated”.
- Between 40,000 to 50,000 patients are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year in the United States. It is the sixth most common cancer worldwide, with an estimated incidence of 500,000 annually. Head and neck cancers include cancers of the oral cavity, oropharynx, hypopharynx, larynx as well as cancers of the nose, paranasal sinuses and salivary glands. Squamous cell carcinomas make up 90% of the head and neck cancers.
- Current treatment protocols for advanced head and neck cancer often entail a disfiguring and risky surgical operation. In addition, radiation therapy and chemotherapy used in conjunction with the surgery results in tremendous morbidity for patients with the disease. Despite best efforts, survival rates for late-stage HNSCC remain dismal. It is apparent that a different approach to treatment is needed.
- Results of clinical studies suggest that single pathway inhibitors are unlikely to be the answer to control these complex tumors, which have multiple molecular level aberrations. There is increasing acknowledgment among cancer researchers that a multi pathway targeting approach is needed to develop effective treatments and prevent resistance and relapses in order to overcome the current limitations of treatment of HNSCC.
- In addition, current immunotherapeutic approaches to treating cancers (e.g., HNSCC), such as the use of checkpoint blockers, has shown unprecedented success in shrinking or halting cancers in some patients. However, these current checkpoint blocker therapies only work in a fraction of patients. Thus, there is a need to increase the effectiveness of these immunotherapeutic approaches so that they may be used alone or in combination with other treatment protocols to treat cancer.
- It is well-accepted that many diseases such as cancer have a high degree of molecular heterogeneity. Oral squamous cell carcinoma (OSCC) is one such cancer where this molecular heterogeneity poses serious challenges to drug designers who traditionally tend to focus on one or a handful of targets that they seek to inhibit or activate. In reality, multiple biochemical species—proteins that play various functions, genes that code for the proteins and their metabolites—are either part of a network and/or part of a biological process cascade. To compound the situation, these targets often continue to mutate and establish alternative signaling pathways in the tumor when a particular pathway is blocked. Thus, it is vital to have a systems-level understanding to address the evolving dynamics of underlying molecular heterogeneity of the tumor. Therefore, to effectively treat the disease, it is important to not only modulate the obvious targets that are mutated or aberrantly expressed and correlated with the pathogenesis of cancer, but also preserve the housekeeping functions of some of these targets, i.e. to down or upregulate the targets only to the extent necessary towards establishing healthy homeostasis as well as block the alternative signaling pathways that can cause future recurrence of the diseases.
- A single-agent drug that can effectively address multiple molecular events in a tumor is virtually impossible given that there is enormous diversity of the binding sites of the targets. Therefore, in treatment of many diseases, particularly in case of cancer, it is fairly common to have a cocktail of drugs wherein different drug molecules work through different mechanisms and on different targets, for example, one or more of those targets identified in
FIG. 10 and/or in Table 2, below. For example, in certain aspects, the compositions disclosed herein modulate one or more of the targets identified in Table 2. However, one of the most common problems associated with such cocktails is that the number of unique molecules in a cocktail is limited to a handful because interactions among these molecules often lead to unwarranted effects. A second issue is that the molecules in the drug cocktail lack true synergy that can overcome the resistance or recurrence mechanisms and produce a durable clinical response. Thus, there is a need for a polypharmaceutical drug containing multiple molecules that are capable of pleiotropic and truly synergistic action to address vast molecular heterogeneity of the tumor and the tumor microenvironment. - Plant-derived drugs used in traditional systems of medicine are naturally occurring polypharmaceuticals. The bioactive molecules in such drugs, which are usually the metabolites produced by the plants, are the result of millions of years of evolution. Nature has explored chemical-diversity space extensively with a vast array of organic/biological scaffolds and through combinatorial biology and under evolutionary selection pressure has produced a chemical library unmatched by any combinatorial library produced by humans. Furthermore, structural scaffolds on which many related compounds are based have been under intense selection, both for targeting selectivity and high potency for many millions of years.
- Plant-derived bioactive molecules generally can be broken down into various classes such as polyphenols, terpenes, alkaloids, sugars, peptides, and large molecules, including proteins and polysaccharides. Many of the molecules have been studied extensively for their medicinal properties. In the case of polyphenols, for example, the following four molecules have been extensively tested for their anti-cancer properties.
- The most well-known example of an anti-cancer drug is Taxol which is a terpenoid.
- While these molecules have shown excellent efficacy for many diseases, they represent reductionist thinking for creating drugs from the botanical sources (see,
FIG. 1 ). However, such a reductionist approach fundamentally fails to leverage the evolutionary advantages of a natural, combination therapeutic. The evolutionary purpose behind the creation of a large diversity of molecules, while producing structurally similar molecules within a single class, is that functional superiority is achieved not by a single molecule, but rather a combination of the molecules. Different molecules play different roles, including increasing pharmacodynamic effect by binding to common or multiple targets in a network, creating redundancy in cases of target mutation, assisting the transport of pharmacodynamic molecules, and improving overall absorption, distribution, metabolism, and excretion (ADME), to name a few. This principle of evolutionary biology—multiple molecules exerting their effect as a part of a system or a consortium of bioactive compounds versus a single, silver-bullet agent—is the basis of designing a polypharmaceutical drug. - A traditional approach for designing a polypharmaceutical drug is the use of a “crude” plant extract as shown in
FIG. 2 . While such a therapeutic drug consists of multiple molecules, the composition of the extracts, as well as the relative ratios, are dependent on and limited by the extraction process used. Such a composition is not optimized for a disease of interest and often lacks sufficient potency. - In a plant, the gene clusters responsible for production of different classes of metabolites generally tend to code for a biosynthetic pathway that produces the molecules belonging to the same class bearing structural similarity. These “co-evolved” molecules are intended to work together functionally. Additionally, different classes of molecules further tend to synergize where each class of molecule is designed to play a distinct role ranging from its versatility in binding to the proteins of interest, to avoidance of the toxicity, to enabling the absorption of the pharmacologically active molecules. While a botanical source produces these compounds in a range of ratios relative to each other, the naturally occurring ratios is not optimized for a human disease of interest, particularly so for a molecularly heterogeneous cancer such as OSCC. Therefore, while a selection of plant(s) with the right classes of pharmacologically active molecules is an important first step in developing a botanical drug, optimizing ratios of different bioactive compounds in the context of the disease biology is vital. Therefore, alteration in natural ratios of the classes of compounds that occur in nature is proposed so as to create new drug where the levels of the compounds are optimized for a given disease of interest.
- In addition to size, conformational flexibility of the molecular backbone, and functional groups that are important in terms of the transport of the molecules and ability to bind to targets, another aspect that determines the physico-chemical properties of the molecules and their ability to act as a drug is relative polarity of the molecules. As shown in
FIG. 3 , the present inventors fractionated the molecules present in a botanical source using the processes that create rich fractions based on their physico-chemical properties. The present inventors then tested the biological activity of the rich fractions separately and in combination to optimize the relative ratios of the active compounds. - Curcuma longa based Botanical Polypharmaceutical Drug
- Based on the foregoing principles, the inventive subject matter comprises the development of a polypharmaceutical drug that primarily uses fractions comprising rich extracts of Curcuma longa, a perennial herb grown in many parts of the world, but in a unique ratio (i.e., different than that found in nature) optimized for treating human diseases. C. longa and more particularly, curcumin, one polyphenolic metabolite from C. longa, is extensively studied for its medicinal properties. While curcumin is often used as a proxy for overall pharmacological properties of C. longa, it is only one of over 200 small bioactive molecules found in C. longa. In keeping with the principles outlined above, and with the objective of creating a polypharmaceutical composition where multiple molecules act synergistically to provide superior pharmacological response, an inventive composition is developed where major classes of molecules from C. longa are combined to create polypharmaceutical compositions.
- The polypharmaceutical compositions comprise a combination of extracts containing low or non-polar compounds, medium polarity compounds, and highly polar compounds in a variety of ratios.
- A low or non-polar extract of C. longa is created by extracting the dried, powdered rhizome with a solvent system that has a dielectric constant less than 5 or a relative polarity of less than 0.2. This extract is rich in a class of compounds known as terpenoids and its concentration is no less than 50% by weight. The extract is usually characterized by the presence and levels of a signature compound Ar-Turmerone.
- An extract rich in medium polarity molecules is obtained by extracting C. longa using a solvent system that has a dielectric constant between 5 and 25 or a relative polarity is equal to or between 0.25 and 0.6. Such an extract is generally rich in a class of compounds known as polyphenols whose concentration ranges from at least 90% curcuminoid and is usually characterized by a signature compound Curcumin. Other examples of polyphenols are described by Li et al., Chemical Composition and Product Quality Control of Turmeric (Curcuma longa L.), Pharmaceutical Crops, 2011, 2:28-54, the entire contents of which incorporated herein by reference.
- An extract rich in high polarity molecules is obtained by extracting C. longa using a solvent system that has a dielectric constant greater than 25 or a relative polarity greater than 0.6. Such an extract is usually rich in nitrogen-containing compounds and polysaccharides whose concentration ranges from 2.5%-15% and at least 25% respectively.
- The values for relative polarity are normalized from measurements of solvent shifts of absorption spectra and are described in Christian Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VCH Publishers, 3rd ed., 2003, the contents of which are incorporated by reference herein.
- Table 1 below summarizes the ratios of the yields of the extracts obtained relative to the weight of the processed starting materials. Approximately only 5% of the desired components are obtained for each type of extract from the raw plant material used.
-
TABLE 1 Summary of Extracts Obtained Using Various Fractionation Processes Ratio of Extracted Product Obtained:Plant Extract material used Signature Molecules High ~1:15 Polysaccharides, Polarity Nitrogen containing compounds Medium ~1:25 Curcuminoids Polarity Low ~1:14 Turmerones Polarity - An exemplary composition, referred to herein as AV1016, was made by combining a high polarity extract, a medium polarity extract and a low polarity extract in a 3:6:1 ratio by weight, respectively, using mechanical blending process. Another exemplary composition, referred to herein as AV2017, was made by combining a high polarity extract, a medium polarity extract and a low polarity extract in a 1:1:1 ratio by weight, respectively, using mechanical blending process.
- Several studies have documented constituent activation of NF-kB in head and neck cancer cell lines. Therefore, it is hypothesized that the inhibition of NF-kB could play an important role in the control of cancer development. Consequently, compositions of varying amounts of different rich extracts were tested for their ability to cause apoptosis of cancer cells in oral cancer cell lines.
- The mechanism of growth suppressive effect of compositions of different ratios of low polarity (LP), medium polarity (MP) and high polarity (HP) extracts was elucidated by measuring the expression of cell cycle, apoptotic and autophagic genes. Protein extracts prepared from cells treated with the fixed, cell-death inducing concentrations of different formulations for the time periods ranging from 2 to 6 hours were analyzed by the gel shift assay to determine the level of NF-kB, P53, P16 and related genes. Protein extracts were also prepared from untreated cells and cells treated with 0.05% DMSO (the amount present in preparations), as controls. The analysis showed a reduction in the level of NF-kB, upregulation in P53 and P16 within 4 hours of treatment followed by a dramatic decrease in NF-kB after 6 hours.
- Phenotypic changes induced by the specific compositions clearly indicate a specific targeting of a definitive gene pathway for cell killing (apoptosis and autophagic signaling axis). The effect of HP, MP, and LP clearly signaled differences in effect on certain genes, with demonstration of synergistic targeting on multiple gene pathways, when combined in some definite proportions.
- Methods of Treatment Using Curcuma longa based Botanical Polypharmaceutical Drug
- Head and Neck Squamous Cell Carcinoma's (HNSCC) and its subset, Oral squamous cell cancer (OSCC) arise through a series of molecular mutations that lead to uncontrolled cellular growth from hyperplasia to dysplasia to carcinoma in situ followed by invasive carcinoma. Major risk factors include tobacco and alcohol consumption along with environmental and genetic factors (Brinkman and Wong, Curr Opin Oncol. 18(3):228-33, 2006; Figuerido et al., Drug Discovery Today Disease Mechanisms 1(2):273-281, November 2004). These cancers are usually detected at late-stages when the disease has advanced and therefore results in poor prognosis and survival.
- Currently, surgery and radiotherapy are the primary treatments, but due to the location in the head and neck this usually results in postoperative defects and functional impairments in patients. Therefore, early disease detection is imperative because it can result in a more effective treatment with superior results.
- Recently, initiatives such as Cancer Genome Atlas (TCGA) have mapped the genome wide effect of individual genes on tumor growth. This provides a framework for unraveling the genomic, transcriptomic, proteomic and metabolomics profile for HNSCC and OSCC.
- The emerging picture reveals significant heterogeneity, which presents challenges for targeted drug treatment, but also opportunities for creating polypharmaceutical compositions to target this heterogeneity.
- The present inventors are studying the effect of AV1016 on wide ranging genomic, transcriptomic, proteomic, and metabolomics markers, including, but not limited to those listed in Table 2, below. Accordingly, in certain aspects, the compositions disclosed herein modulate or otherwise affect one or more of the pathways listed in Table 2. In certain embodiments, the compositions disclosed herein modulate the expression (e.g., increase or decrease the expression) of one or more of the biomarkers listed in Table 2.
-
TABLE 2 Potential Pathways Impacted by AV1016 and Examples of Reporter Molecules and Biomarkers for Assessing Impact Pathways and Factors Example Reporter Biomarkers Chemokine receptors CXCR2 CXCR4 CCR7 Viral HPV, EBV Methylation markers Metalloproteinases MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10 Interleukins IL-6, IL-8 IL-1, IL-1Beta, MicroRNA's miR-106b-25 cluster, miR-375, miR451, miR-125a, miE- 200a, miR-205, miR-138, Melanoma Associated MAGE Genes Centrosome abnormalities Cytokeratins Oncogenes and Tumor TP53, NOTCH1, CDKN2A suppressor genes Genes implicated in cell CDKN2A, RB1, CDK12, CDKN1B, CCND1, CDKN1A, cycle CDKN2C, Ki67/MIB-1, AgNORs, Cyclin D1, VRK1, EGFR, EGFR variants, K-RAS, NF-KB, AURKA/STK15/BTAK, ERCC1, XRCC1 Angiogenic factors VEGF, HIF-1 Structural related EMT, b-Tubulin, CD 44, CD 68 markers Epigenetic modifiers Aberrant DNA methylation, Histone modifications and miRNAs Transcription VHL, NFKB, Factors/regulators GATA3, TSHZ3, EP300, CTCF, TAF1, TSHZ2, RUNX1, MECOM, TBX3, SIN3A, WT1, EIF4A2, FOXA1, PHF6, CBFB, SOX9, ELF3, VEZF1, CEBPA, FOXA2 Histone Modifier MLL3, MLL2, ARID1A, PBRM1, SETD2, NSD1, SETBP1, KDM5C, KDM6A, MLL4, ARID5B, ASXL1, EZH2 Genome Integrity TP53, ATM, ATRX, BRCA2, ATR, STAG2, BAP1, BRCA1, SMC1A, SMC3, CHEK2, RAD21, ERCC2 MAPK signaling KRAS, NF1, MAP3K1, BRAF, NRAS, MAP2K4, MAPK81P1 PI(3)K signaling PIK3CA, PTEN, PIK3R1, TLR4, PIK3CG, AKT1 TGF-Beta signaling SMAD4, TGFBR2, ACVR1B, SMAD2, ACVR2A Wnt/Beta-catenin APC, CTNNB1, AXIN2, TBL1XR1, SOX17, signaling Histone HIST1HIC, H3F3C, HIST1H2BD Proteolysis FBXW7, KEAP1, SPOP Splicing SF3B1, U2AF1, PCBP1, HIPPO signaling CDH1, AJUBA DNA methylation DNMT3A, TET2 Metabolism/Metabolites IDH1, IDH2, Intercept, Alanine, Choline, Leucine + Isoleucine, Glutamic Acid, 120,0801 m/z, PhenylAlanine, alpha-Aminobutyric acid, Serine, Trimethylymine, Piperidine NFE2L NFE2L2, NFE2L3 Protein phosphatase PPP2R1A, PTPN11 Ribosome RPL22, RPL5 TOR signaling MTORSTK11 Other TNF-A, NFKB, Bmi-1, P16, NAV3, LRRK2, MALAT1, ARHGAP35, POLQ, NCOR1, USP9X, NPM1, HGF, EPPK1, AR, LIFR, PRX, CRIPAK, EGR3, B4GALT3, MIR142, GAN, TIMP4, BCL-XL, BCL-2, BAX, CA9, TP53BP2, HOXB9, NFKB1A
Use of Curcuma longa based Botanical Polypharmaceutical Drug to Prime Tumors - Currently available cancer therapies generally involve multiple treatment modalities, which may include immunotherapeutics. Immunotherapy drugs belonging to a group called checkpoint inhibitors are antibody-based agents that mobilize the immune T-cell response. Checkpoint mechanisms, such as those based on PD-1 and PD-L1, are the body's normal mechanisms to prevent T cells from attacking healthy tissues. However, cancer cells are able to hijack this mechanism by sending false signals to the body's T cells, thereby masquerading cancer cells as normal, non-cancerous cells. The immune system responds by turning the T cell and other macrophages off, allowing cancer cells to multiply. Checkpoint inhibitors, by various mechanisms, make these cancer cells recognizable and thus, allow the immune system (e.g., T cells), to activate and thus destroy cancer cells.
- However, checkpoint inhibitors are not necessarily effective for all patients. One reason checkpoint inhibitors may be ineffective is that cancerous tumor may have a limited number of T cells to be turned on. Tumors may be termed “hot” when they are filled with T cells and “cold” when they contain only a few T cells. The classifying of a tumor as “cold” or “hot” can be referred to as an immunoscore. “Hot” tumors are generally more sensitive to immunotherapy due to the increased amount of T cells, and therefore patients with “hot” tumors tend to respond to immunotherapy, such as that based on checkpoint inhibitors, better than patients with “cold” tumors.
- One way to address this issue is to make cold tumors “hot,” or in other words to prime the tumor. Priming the tumor may result in an increase in the number of T cells present within the tumor. Surprisingly it has been found that AV1016 acts as a primer of tumors. For example, administration of AV1016 to a patient resulted in a tumor changing from “cold” to “hot,” as illustrated in
FIG. 12 . The patient, a 64-year old male with a history of smoking, had a biopsy tissue sample removed from a tumor in the floor of his mouth (pre-AV1016 administration). The patient then returned to the clinic approximately two weeks later for a scheduled surgical procedure. However, prior to the surgical procedure, the patient was administered AV1016 (600 mg dose) delivered in a hydrogel carrier to the oral cavity of the patient. Approximately 24 hours after receiving AV1016, the patient underwent surgical resection of his tumor (post-AV1016 administration). The pre- and post-AV1016 immunofluorescence results illustrated inFIG. 12 evidence that the patient's tumor changed from “cold” to “hot” after administration of AV1016. Thus, AV1016 demonstrated efficacy as a primer of tumors for use in combination with other immunotherapies.
Claims (20)
1. A pharmaceutical composition comprising: (a) one or more high polarity compounds isolated from Curcuma longa selected from the group consisting of peptides, polysaccharides, and proteins; (b) one or more medium polarity compounds isolated from Curcuma longa selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and (c) one or more non-polar compounds isolated from Curcuma longa selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone; wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
2. The composition of claim 1 , wherein the one or more high polarity compounds are isolated from Curcuma longa using a high polarity solvent system having a dielectric constant of greater than about 25 and a relative polarity value of less than about 0.6.
3. The composition of claim 1 , wherein the one or more medium polarity compounds are isolated from Curcuma longa using a medium polarity solvent system having a dielectric constant of about 5 to about 25 and a relative polarity value of about 0.25 to about 0.6.
4. The composition of claim 1 , wherein the one or more non-polar compounds are isolated from Curcuma longa using a non-polar solvent system having a dielectric constant of less than about 5 and a relative polarity value of less than about 0.2.
5. A method of treating cancer or a pre-cancerous condition, the method comprising administering an effective amount of the composition of claim 1 to a subject in need thereof, thereby treating the cancer or pre-cancerous condition.
6. The method of claim 5 , wherein the cancer is oral squamous cell carcinoma.
7. The method of claim 5 , wherein the pre-cancerous condition is leukoplakia.
8. The method of claim 5 , wherein the composition is administered in combination with a chemotherapy or immunotherapy agent.
9. The method of claim 8 , wherein the immunotherapy agent is selected from the group consisting of checkpoint inhibitors, checkpoint blockers, vaccines and CAR-T cells.
10. The method of claim 8 , wherein the composition promotes or increases T-cell infiltration in a tumor of the subject.
11. The method of claim 8 , wherein the composition increases sensitivity of a tumor to the chemotherapy or immunotherapy agent.
12. A composition for use in treating oral squamous cell carcinoma, wherein the compositions comprises:
a. one or more high polarity compounds isolated from Curcuma longa selected from the group consisting of peptides, polysaccharides, and proteins;
b. one or more medium polarity compounds isolated from Curcuma longa selected from the group consisting of polyphenols, curcumin, demethoxycurcumin, and bisdemethoxycurcumin; and
c. one or more non-polar compounds isolated from Curcuma longa selected from the group consisting of terpenoids, ar-turmerone, α-turmerone, and β-turmerone;
wherein the composition comprises a ratio of the high polarity compounds, medium polarity compounds and non-polar compounds selected from the group consisting of about [1]:[1]:[1] by weight and about [3]:[6]:[1] by weight.
13. The composition of claim 12 , wherein the one or more high polarity compounds are isolated from Curcuma longa using a high polarity solvent system having a dielectric constant of greater than about 25 and a relative polarity value of less than about 0.6.
14. The composition of claim 12 , wherein the one or more medium polarity compounds are isolated from Curcuma longa using a medium polarity solvent system having a dielectric constant of about 5 to about 25 and a relative polarity value of about 0.25 to about 0.6.
15. The composition of claim 12 , wherein the one or more non-polar compounds are isolated from Curcuma longa using a non-polar solvent system having a dielectric constant of less than about 5 and a relative polarity value of less than about 0.2.
16. The composition of claim 12 , wherein the composition is formulated for oral administration to a subject.
17. The composition of claim 12 , wherein the composition is formulated for buccal administration to a subject.
18. The composition of claim 12 , wherein the composition is formulated for transdermal administration.
19. The composition of claim 12 , wherein the composition comprises about 11-15% w/w of the high polarity polysaccharides, about 41-44% w/w of the medium polarity compound curcumin, and about 3-4% w/w of the non-polar compound ar-tumerone.
20. The composition of claim 12 , wherein upon administration to a subject the composition promotes or increases T-cell infiltration in a tumor of the subject.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/209,360 US20230321177A1 (en) | 2018-04-02 | 2023-06-13 | Polypharmaceutical drug compositions and related methods |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862651683P | 2018-04-02 | 2018-04-02 | |
PCT/US2019/025465 WO2019195349A1 (en) | 2018-04-02 | 2019-04-02 | Polypharmaceutical drug compositions and related methods |
US202017044696A | 2020-10-01 | 2020-10-01 | |
US18/209,360 US20230321177A1 (en) | 2018-04-02 | 2023-06-13 | Polypharmaceutical drug compositions and related methods |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/044,696 Continuation US11701402B2 (en) | 2018-04-02 | 2019-04-02 | Polypharmaceutical drug compositions and related methods |
PCT/US2019/025465 Continuation WO2019195349A1 (en) | 2018-04-02 | 2019-04-02 | Polypharmaceutical drug compositions and related methods |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230321177A1 true US20230321177A1 (en) | 2023-10-12 |
Family
ID=68101348
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/044,696 Active 2039-04-24 US11701402B2 (en) | 2018-04-02 | 2019-04-02 | Polypharmaceutical drug compositions and related methods |
US18/209,360 Pending US20230321177A1 (en) | 2018-04-02 | 2023-06-13 | Polypharmaceutical drug compositions and related methods |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/044,696 Active 2039-04-24 US11701402B2 (en) | 2018-04-02 | 2019-04-02 | Polypharmaceutical drug compositions and related methods |
Country Status (4)
Country | Link |
---|---|
US (2) | US11701402B2 (en) |
EP (1) | EP3773654B1 (en) |
ES (1) | ES2966025T3 (en) |
WO (1) | WO2019195349A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3773654B1 (en) | 2018-04-02 | 2023-09-20 | Aveta Biomics, Inc. | Polypharmaceutical drug compositions and related methods |
US20220193177A1 (en) * | 2019-04-01 | 2022-06-23 | Aveta Biomics, Inc. | Methods and compositions for treating dysbiosis of oral microbiome |
US20230061121A1 (en) * | 2019-05-15 | 2023-03-02 | The Regents Of The University Of California | Methods concerning ongoing treatment for cancer |
US11977085B1 (en) | 2023-09-05 | 2024-05-07 | Elan Ehrlich | Date rape drug detection device and method of using same |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR57704E (en) | 1942-03-20 | 1953-05-04 | Int Standard Electric Corp | Methods for determining the position of obstacles by reflected electromagnetic waves |
US7744931B2 (en) | 2005-06-14 | 2010-06-29 | New Chapter Inc. | Methods for treating oral cancers with herbal compositions |
US20080193573A1 (en) | 2006-03-17 | 2008-08-14 | Gow Robert T | Extracts and methods comprising curcuma species |
US20160151440A1 (en) | 2013-08-19 | 2016-06-02 | Aurea Biolabs Private Limited | A Novel Composition of Curcumin with Enhanced Bioavailability |
IN2013MU01590A (en) | 2013-11-02 | 2015-08-07 | Jatin Vasant Thakkar | |
WO2015076430A1 (en) | 2013-11-20 | 2015-05-28 | 가톨릭대학교 산학협력단 | Composition for preventing or treating immune diseases, containing metformin as active ingredient |
US20160256513A1 (en) | 2015-03-04 | 2016-09-08 | The Synergy Company of Utah, LLC d/b/a Synergy Production Laboratories | Synergized turmeric |
EP3773654B1 (en) | 2018-04-02 | 2023-09-20 | Aveta Biomics, Inc. | Polypharmaceutical drug compositions and related methods |
-
2019
- 2019-04-02 EP EP19780582.3A patent/EP3773654B1/en active Active
- 2019-04-02 WO PCT/US2019/025465 patent/WO2019195349A1/en unknown
- 2019-04-02 US US17/044,696 patent/US11701402B2/en active Active
- 2019-04-02 ES ES19780582T patent/ES2966025T3/en active Active
-
2023
- 2023-06-13 US US18/209,360 patent/US20230321177A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2019195349A1 (en) | 2019-10-10 |
US11701402B2 (en) | 2023-07-18 |
EP3773654B1 (en) | 2023-09-20 |
EP3773654A1 (en) | 2021-02-17 |
EP3773654C0 (en) | 2023-09-20 |
ES2966025T3 (en) | 2024-04-18 |
US20210252097A1 (en) | 2021-08-19 |
EP3773654A4 (en) | 2021-11-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230321177A1 (en) | Polypharmaceutical drug compositions and related methods | |
US7067159B2 (en) | Methods for treating prostate cancer with herbal compositions | |
EP0393575B1 (en) | Neoplasia treatment compositions containing antineoplastic agent and side-effect reducing protective agent | |
CN102078305B (en) | Bendamustine pharmaceutical compositions | |
US6469040B2 (en) | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia | |
CN100558356C (en) | The method that using cyclooxygenase-2-inhibitor 2 treatment and prophylaxis of tumours form | |
US7744931B2 (en) | Methods for treating oral cancers with herbal compositions | |
US7622142B2 (en) | Methods for treating glioblastoma with herbal compositions | |
US8815827B2 (en) | Myeloid differentiation inducing agents | |
US9029345B2 (en) | Selective inhibitors of translesion DNA replication | |
US20080233221A1 (en) | Prostate cancer and benign prostatic hyperplasia treatments | |
KR20060136395A (en) | Methods for Treating Prostate Cancer with Herbal Compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: AVETA BIOMICS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MEHTA, PARAG G.;MUDGAL, SHARMILA;HINGORANI, LAL;AND OTHERS;SIGNING DATES FROM 20190624 TO 20190703;REEL/FRAME:064914/0563 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |