CN105744958B - 新颖医药组成物及其用途 - Google Patents
新颖医药组成物及其用途 Download PDFInfo
- Publication number
- CN105744958B CN105744958B CN201380047401.6A CN201380047401A CN105744958B CN 105744958 B CN105744958 B CN 105744958B CN 201380047401 A CN201380047401 A CN 201380047401A CN 105744958 B CN105744958 B CN 105744958B
- Authority
- CN
- China
- Prior art keywords
- npm
- cancer
- cell
- inhibitor
- performance
- 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.)
- Expired - Fee Related
Links
- 239000000470 constituent Substances 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 claims abstract description 39
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 28
- 230000005907 cancer growth Effects 0.000 claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 55
- 201000011510 cancer Diseases 0.000 claims description 32
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 19
- 229960004891 lapatinib Drugs 0.000 claims description 19
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 19
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 12
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 201000007270 liver cancer Diseases 0.000 claims description 12
- 208000014018 liver neoplasm Diseases 0.000 claims description 12
- 229960003787 sorafenib Drugs 0.000 claims description 12
- GEZHEQNLKAOMCA-RRZNCOCZSA-N (-)-gambogic acid Chemical compound C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(\C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-RRZNCOCZSA-N 0.000 claims description 9
- GEZHEQNLKAOMCA-UHFFFAOYSA-N epiisogambogic acid Natural products O1C2(C(C3=O)(CC=C(C)C(O)=O)OC4(C)C)C4CC3C=C2C(=O)C2=C1C(CC=C(C)C)=C1OC(CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-UHFFFAOYSA-N 0.000 claims description 9
- GEZHEQNLKAOMCA-GXSDCXQCSA-N gambogic acid Natural products C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(/C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-GXSDCXQCSA-N 0.000 claims description 9
- QALPNMQDVCOSMJ-UHFFFAOYSA-N isogambogic acid Natural products CC(=CCc1c2OC(C)(CC=C(C)C)C=Cc2c(O)c3C(=O)C4=CC5CC6C(C)(C)OC(CC=C(C)/C(=O)O)(C5=O)C46Oc13)C QALPNMQDVCOSMJ-UHFFFAOYSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 7
- 229940043355 kinase inhibitor Drugs 0.000 claims description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 108020004459 Small interfering RNA Proteins 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000012217 deletion Methods 0.000 claims description 2
- 230000037430 deletion Effects 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 102100022678 Nucleophosmin Human genes 0.000 abstract description 7
- 108010025568 Nucleophosmin Proteins 0.000 abstract description 7
- 208000024891 symptom Diseases 0.000 abstract description 7
- 210000004027 cell Anatomy 0.000 description 86
- 210000003470 mitochondria Anatomy 0.000 description 22
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 18
- 230000000694 effects Effects 0.000 description 15
- 238000002560 therapeutic procedure Methods 0.000 description 15
- 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 14
- 230000037396 body weight Effects 0.000 description 14
- 238000012545 processing Methods 0.000 description 13
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 11
- KZOLQEUQAFTQFM-UHFFFAOYSA-N n,n,n',n'-tetrakis[(6-methyl-1h-benzimidazol-2-yl)methyl]ethane-1,2-diamine Chemical compound C1=C(C)C=C2NC(CN(CCN(CC=3NC4=CC(C)=CC=C4N=3)CC=3NC4=CC(C)=CC=C4N=3)CC3=NC4=CC=C(C=C4N3)C)=NC2=C1 KZOLQEUQAFTQFM-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 230000006907 apoptotic process Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 210000000172 cytosol Anatomy 0.000 description 8
- -1 that is Substances 0.000 description 8
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 7
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 7
- 210000000805 cytoplasm Anatomy 0.000 description 7
- 229910052697 platinum Inorganic materials 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 230000002195 synergetic effect Effects 0.000 description 7
- 240000001717 Vaccinium macrocarpon Species 0.000 description 6
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 6
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 6
- 235000004634 cranberry Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 201000010881 cervical cancer Diseases 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 229960004857 mitomycin Drugs 0.000 description 5
- 238000006384 oligomerization reaction Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 238000000749 co-immunoprecipitation Methods 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 230000030279 gene silencing Effects 0.000 description 4
- 238000001325 log-rank test Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RTYFJRNBENOOIZ-NSHDSACASA-N (3S)-1-[4-(aminomethyl)phenyl]sulfonylpiperidin-3-ol Chemical compound C1C[C@@H](CN(C1)S(=O)(=O)C2=CC=C(C=C2)CN)O RTYFJRNBENOOIZ-NSHDSACASA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960002584 gefitinib Drugs 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009182 swimming Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 108091012583 BCL2 Proteins 0.000 description 2
- 108010011730 CIGB-300 Proteins 0.000 description 2
- RNELHWXSRSKXRD-QNKYCTLBSA-N CIGB-300 Chemical group C([C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)=O)CCSC)NC(=O)CCNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CN)C(O)=O)[C@@H](C)O)C1=CNC=N1 RNELHWXSRSKXRD-QNKYCTLBSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 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
- 101150029707 ERBB2 gene Proteins 0.000 description 2
- 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 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010824 Kaplan-Meier survival analysis Methods 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 101710086987 X protein Proteins 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 230000002424 anti-apoptotic effect Effects 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- 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 2
- 239000002585 base Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000000546 chi-square test Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 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 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- XHWRWCSCBDLOLM-UHFFFAOYSA-N nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 description 2
- 229950000891 nolatrexed Drugs 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 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 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 210000003240 portal vein Anatomy 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000012622 synthetic inhibitor Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- NJZQOCCEDXRQJM-UHFFFAOYSA-N 1-benzylindole Chemical class C1=CC2=CC=CC=C2N1CC1=CC=CC=C1 NJZQOCCEDXRQJM-UHFFFAOYSA-N 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- VLDBEZDOSUKOBS-UHFFFAOYSA-O 2-(3-hydroxyphenyl)ethyl-trimethylazanium Chemical compound C[N+](C)(C)CCC1=CC=CC(O)=C1 VLDBEZDOSUKOBS-UHFFFAOYSA-O 0.000 description 1
- PJKVJJYMWOCLIJ-UHFFFAOYSA-N 2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1h-quinazolin-4-one;hydron;dichloride Chemical compound Cl.Cl.CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 PJKVJJYMWOCLIJ-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000052052 Casein Kinase II Human genes 0.000 description 1
- 108010010919 Casein Kinase II Proteins 0.000 description 1
- 102100024246 Caspase activity and apoptosis inhibitor 1 Human genes 0.000 description 1
- 101710196418 Caspase activity and apoptosis inhibitor 1 Proteins 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 108010093099 Endoribonucleases Proteins 0.000 description 1
- 108091062183 EsiRNA Proteins 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 238000012752 Hepatectomy Methods 0.000 description 1
- 101000960337 Homo sapiens Intercellular adhesion molecule 5 Proteins 0.000 description 1
- 102100039919 Intercellular adhesion molecule 5 Human genes 0.000 description 1
- 238000012313 Kruskal-Wallis test Methods 0.000 description 1
- UCEQXRCJXIVODC-PMACEKPBSA-N LSM-1131 Chemical compound C1CCC2=CC=CC3=C2N1C=C3[C@@H]1C(=O)NC(=O)[C@H]1C1=CNC2=CC=CC=C12 UCEQXRCJXIVODC-PMACEKPBSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229910020700 Na3VO4 Inorganic materials 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 102000009097 Phosphorylases Human genes 0.000 description 1
- 108010073135 Phosphorylases Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101710092489 Protein kinase 2 Proteins 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- LHHQTXPEHJNOCX-UHFFFAOYSA-N Rottlerin Natural products CC(=O)c1c(O)c(C)c(O)c(Oc2c(O)c3C=CC(C)(C)Cc3c(C(=O)C=Cc4ccccc4)c2O)c1O LHHQTXPEHJNOCX-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 241000545067 Venus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 102000055102 bcl-2-Associated X Human genes 0.000 description 1
- 108700000707 bcl-2-Associated X Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000005782 double-strand break Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- XPLYQICAQFRBTJ-WAFAGKNESA-N ethyl (6aR)-1-methoxy-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-6-carboxylate Chemical compound O=C(OCC)N1[C@H]2c3c(c(OC)c(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)cc3CC1)-c1c(cccc1)C2 XPLYQICAQFRBTJ-WAFAGKNESA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 231100000652 hormesis Toxicity 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XPLYQICAQFRBTJ-UHFFFAOYSA-N kamaline Natural products CCOC(=O)N1CCc2cc(OC3OC(CO)C(O)C(O)C3O)c(OC)c4c2C1Cc5ccccc45 XPLYQICAQFRBTJ-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011976 maleic acid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 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 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000016670 prohibitin Human genes 0.000 description 1
- 108010028138 prohibitin Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000000637 radiosensitizating effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- DEZFNHCVIZBHBI-ZHACJKMWSA-N rottlerin Chemical compound CC(=O)C1=C(O)C(C)=C(O)C(CC=2C(=C(C(=O)\C=C\C=3C=CC=CC=3)C=3OC(C)(C)C=CC=3C=2O)O)=C1O DEZFNHCVIZBHBI-ZHACJKMWSA-N 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229950005976 tivantinib 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
- 238000012546 transfer Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- 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
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0613—Apparatus adapted for a specific treatment
- A61N5/062—Photodynamic therapy, i.e. excitation of an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
- A61N2005/0661—Radiation therapy using light characterised by the wavelength of light used ultraviolet
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
- C12N2320/31—Combination therapy
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明揭示一种医药组成物,其含有NPM抑制剂与抗癌剂的组合。本发明亦提供抑制或减少个体中癌细胞生长的方法,该方法借由投予有效量的核仁磷酸蛋白(NPM)抑制剂及一或多种抗癌剂,借此减轻该个体的症状及征象来进行。
Description
本申请案主张2012年9月13日申请的美国申请案第 61/700,756号的权益,该案的全部揭示内容以引用的方式并入本文中。
背景技术
核仁磷酸蛋白(nucleophosmin,NPM)为主要位于核仁中的高度保守磷蛋白,且在细胞周期期间在核仁与细胞质之间穿梭。其牵涉于核糖体生物发生、中心体复制、基因组稳定性及细胞凋亡的调节中。
癌症仍为世界范围的主要公众健康问题。其深切影响美国每年诊断的超过1,000,000人,以及其家人及朋友。尽管在过去的 50年中化学疗法已有所进展,但医学界仍面临治疗许多类型的癌症的挑战。因此,仍需要更有效且安全的癌症治疗。本发明解决此需要。
发明内容
一些具体实例提供一种医药组成物,其包含一或多种NPM抑制剂及一或多种抗癌剂。此组合宜对癌症抑制具有累加或协同作用。
一些具体实例提供减少或抑制癌症生长的方法,其包含向有需要的个体投予有效量的NPM抑制剂及有效量的抗癌剂,从而减少或抑制癌症生长。
附图说明
图1A展示在曝露于UV-B、顺铂(cisplatin)或小红莓 (doxorubicin)后,肝癌细胞中NPM及BCL2相关X蛋白(BCL2-associated X protein,BAX)的表现。图1B展示UV-B 照射前(左图)、UV-B照射后3小时(中间图)及UV-B照射后 6小时(右图)的NPM亚细胞分布。NPM的亚组在UV照射后6 小时移位至细胞质(由右图中的箭头指示)。图1C展示BAX(上图)、线粒体(中间图)以及BAX及线粒体(下图)的亚细胞分布。
图2示意性说明涉及NPM及BAX的细胞内细胞凋亡及死亡逃避路径。
图3展示在使用或不使用UV辐射(UVB)、丝裂霉素C (mitomycin C)(MMC)、小红莓(DOXO)或顺铂(CDDP) 处理的情形下,siNS(含有错义序列的siRNA)及siNPM(抑制 NPM表现的siRNA)对肝癌细胞的作用。
图4展示在使用或不使用UVB、MMC、DOXO或CDDP处理的情形下,siNS(含有错义序列的siRNA)、siNPM(抑制NPM 表现的siRNA)、siTP53(以p53为目标的siRNA)及siNPM与siTP53的组合对肝癌细胞的作用。
图5展示正常肝细胞(C)、肝癌细胞(T)及副肝癌细胞(N) 的NPM表现。
图6展示在UV照射后,肝癌细胞中NPM表现阻断BAX的线粒体移位及寡聚。图6A说明在使用或不使用错义序列(NS) siRNA或以NPM为目标的siRNA的情形下,在UV照射后,Mahlavu肝癌细胞的细胞溶质及线粒体中的NPM及BAX表现。图6B说明siNPM及siNS对线粒体或核中的BAX二聚物(以星号表示)及BAX寡聚物(双星号)的作用。
图7展示siNS及siNPM对使用或不使用目标癌症疗法(索拉非尼(Sorafenib)及拉帕替尼(Lapatinib))处理的肝癌细胞(Hep3B、 Huh7及Mahlavu)的作用。
具体实施方式
定义
如上文及本发明全文所用,除非另外指出,否则以下术语应理解为具有以下含义。
本专利中所用的术语“本发明(invention/the invention/this invention/thepresent invention)”意欲大致指本专利及下文主张的专利的所有主题。应理解含有此等术语的陈述并不限制本文所述的主题或限制下文的专利申请专利范围的含义或范畴。本专利涵盖的本发明的具体实例由下文的申请专利范围而非本说明书定义。本说明书不欲鉴别所主张主题的基本特征,亦不为单独用于判断所主张主题的范畴的本说明书的任何部分。应借由参考整个说明书的适当部分(包括所有正文及图式及申请专利范围每一项)来理解所主张主题。
如本文所用,除非上下文另外明确指出,否则单数形式“一 (a/an)”及“该(the)”包括复数个指示物。
如本文所用,“有效量(effective amount)”包括足以减轻癌症的症状及/或征象的NPM抑制剂或抗癌剂的剂量。
如本文所用,术语“治疗(treating/treated/treatment)”包括预防性(例如防治性)、缓解性及治愈性用途或结果。
术语“抑制(inhibiting/suppressing)”包括减缓或停止生长。
术语“个体(subject)”包括患有癌症或处于发展癌症的风险中的脊椎动物。个体较佳为温血动物,包括哺乳动物,较佳为人类。
术语医药组成物的酸性治疗剂的“医药学上可接受的盐 (pharmaceuticallyacceptable salts)”为与碱形成的盐,亦即碱加成盐,诸如碱金属盐及碱土金属盐,诸如钠盐、锂盐、钾盐、钙盐、镁盐,以及4铵盐,诸如铵盐、三甲基铵盐、二乙基铵盐及参-(羟甲基)-甲基-铵盐。类似地,亦可向具有作为结构的一部分的组成部分(诸如吡啶基)的碱性治疗剂提供诸如无机酸、有机羧酸及有机磺酸(例如盐酸、甲烷磺酸、顺丁烯二酸)的酸加成盐的酸加成盐。
医药组成物
本发明的一些具体实例是针对用于减少或抑制癌细胞生长的医药组成物。这些医药组成物包含至少一种NPM抑制剂与至少一种抗癌剂的组合。NPM抑制剂及抗癌剂可产生累加或协同作用。
NPM抑制剂
NPM抑制剂为减少或减缓NPM表现及/或降低NPM活性的任何试剂。在一个具体实例中,NPM抑制剂为(Z)-5-((N-苯甲基-1H- 吲哚-3-基)亚甲基)咪唑啶-2,4-二酮衍生物或其医药学上可接受的盐。在另一具体实例中,NPM抑制剂为5-((N-苯甲基-1H-吲哚-3- 基)亚甲基)嘧啶-2,4,6(1H,3H,5H)三酮衍生物或其医药学上可接受的盐,其在吲哚与N-苯甲基部分两者中并入多种取代基,这些取代基揭示于Sekhar等人,“The Novel ChemicalEntity YTR107 Inhibits Recruitment of Nucleophosmin to Sites of DNA Damage,Suppressing Repair of DNA Double-Strand Breaks and EnhancingRadiosensitization”Clin Cancer Res 2011;17:6490-6499中。在另一具体实例中,NPM抑制剂为NSC 348884或其医药学上可接受的盐,其揭示于美国专利第8,063,089号中且以全文引用的方式并入本文中。在另一具体实例中,NPM抑制剂为CIGB-300,即在细胞内传递后削弱CK2磷酸化的环肽。CIGB-300的合成描述于Perea等人“Antitumor effect of a novelproapoptotic peptide that impairs the phosphorylation by the protein kinase 2(casein kinase 2).Cancer Res 2004;64:7127-9”中且以全文引用的方式并入本文中。在另一具体实例中,NPM抑制剂为藤黄酸(Gambogic acid)或医药学上可接受的盐。
在一些具体实例中,NPM抑制剂为以NPM RNA转录为目标以降低NPM表现的小干扰RNA(例如siRNA、短干扰RNA或沉默RNA)。在另一具体实例中,NPM抑制剂为以NPM为目标的小干扰RNA的生物合成前驱物。小干扰RNA典型地为具有磷酸化5'端及羟基化3'端且具有两个或两个以上突出核苷酸的双股短 RNA物质。在一些具体实例中,NPM抑制剂为包含s9676的siRNA (SEQ ID NO:2及3),其中SEQ ID NO:2表示有义股且SEQ ID NO:3表示反义股。在一些具体实例中,NPM抑制剂为包含s9677 的siRNA(SEQ ID NO:4及5),其中SEQ ID NO:4表示有义股且SEQ ID NO:5表示反义股。在一些具体实例中,NPM抑制剂为任何RNA物质,诸如(但不限于)微RNA(miRNA)、短发夹RNA、核糖核酸内切酶制备的siRNA(esiRNA)、天然反义短干扰RNA(natsiRNA),其中RNA物质以NPM RNA转录为目标以降低NPM表现。
在一具体实例中,NPM抑制剂为5-((N-苯甲基-1H-吲哚-3-基) 亚甲基)嘧啶-2,4,6(1H,3H,5H)三酮(表示为YTR107,参看式(I))。
抗癌剂
抗癌剂包括已知化学治疗剂、目标癌症疗法或放射疗法。
已知化学治疗剂包含蒽环霉素(anthracycline)抗生素、DNA 合成抑制剂、烷基化剂、抗叶酸剂、代谢抑制剂或其组合。
蒽环霉素抗生素的实例包括(但不限于)小红莓、表柔比星 (Epirubicin)、米托蒽醌(Mitoxantrone)及其类似物。
DNA合成抑制剂的实例包括(但不限于)丝裂霉素C (mitomycin C)、5FU(5-氟尿嘧啶)、卡培他滨(Capecitabine)、伊立替康盐酸盐(Irinotecan hydrochloride)、塞米太克(thymitaq) 及其类似物。
烷基化剂的实例包括(但不限于)顺铂、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、米托蒽醌及其类似物。
代谢抑制剂的实例包括(但不限于)依托泊苷(etoposide)、卡马拉素(rottlerin)及其类似物。
抗叶酸剂的实例包括(但不限于)洛拉曲克(Nolatrexed)及其类似物。
目标癌症疗法为借由干扰癌发生及癌症生长所需的特定目标分子,而非借由简单干扰快速分化细胞(例如使用已知化学治疗剂)来抑制癌细胞生长的药疗法。在一些具体实例中,目标癌症疗法包含激酶抑制剂、血管生成抑制剂、表皮生长因子受体 (epidermalgrowth factor receptor,EGFR)抑制剂、HER2/neu 受体或其组合。
激酶抑制剂的实例包括(但不限于)吉非替尼(gefitinib)、拉帕替尼、索拉非尼、舒尼替尼(sunitinib)、厄洛替尼(erlotinib)、 ABT-869、ARQ 197及其类似物。
血管生成抑制剂的实例包括(但不限于)阿瓦斯丁(Avastin)、布立尼布(Brivanib)、贝伐单抗(Bevacizumab)、礼来单抗 (Ramucirumab)及其类似物。
EGFR抑制剂的实例包括(但不限于)吉非替尼、西妥昔单抗 (Cetuximab)及其类似物。
HER2/neu受体的实例包括(但不限于)曲妥珠单抗 (Trastuzumab)、拉帕替尼或其类似物。
抗癌剂的副作用已知,诸如重量减轻、毛发脱落、贫血、嗜中性球减少症及血小板减少症。此等副作用可借由投予较低剂量的抗癌剂与一或多种NPM抑制剂的组合来克服,从而实现所要治疗作用。观察到的包含NPM抑制剂与抗癌剂(例如顺铂)的组合的医药组成物的协同或累加作用可提供对癌细胞生长的有效抑制或减少,其中当各别抗癌剂在单一疗法中使用时,一个或甚至所有较低剂量的抗癌剂将不足以具有治疗作用。
待根据本文提供的一些具体实例的方法投予的医药组成物可容易使用医药学上可接受的载剂调配、制备或与其一起投予。这些医药组成物可借由多种技术制备。这些技术包括使医药组成物的活性组分(诸如NPM抑制剂)与医药学上可接受的载剂缔合。在一个具体实例中,借由使医药组成物的活性组分与液体载剂、固体载剂或两者均匀及密切缔合来制备医药组成物。液体载剂包括(但不限于)水性调配物、非水性调配物或两者。固体载剂包括(但不限于)生物载剂、化学载剂或两者。
医药组成物在水性悬浮液、油乳液、油包水乳液及水包油包水乳液中,及在包括(但不限于)乳霜、凝胶、脂质体(中性、阴离子性或阳离子性)、脂质纳米球体或微球体、中性、阴离子性或阳离子性聚合纳米粒子或微粒、特定位点乳液、长时间滞留乳液、粘稠乳液、微乳液、纳米乳液、微球体、纳米球体、纳米粒子及小型泵的载剂中,且与允许持续释放医药组成物的多种天然或合成聚合物(包括阴离子性、中性或阳离子性多糖及阴离子性、中性、阳离子性聚合物或共聚物)一起投予,其中这些小型泵或聚合物在需要传递组成物的处的附近植入。此外,本文提供的医药组成物的活性组分适于与任一种载剂或任何载剂组合一起使用。此等载剂包括(但不限于)抗氧化剂、缓冲液及抑菌剂,且视情况包括悬浮剂、增稠剂或防腐剂。
对于在非水性载剂中投药而言,用矿物油或与中性油(诸如 (但不限于)二甘油酯、三甘油酯、磷脂、脂质、油及其混合物) 使本文提供的医药组成物的活性组分乳化,其中该油含有多不饱和脂肪酸与多饱和脂肪酸的适当混合物。实例包括(但不限于) 大豆油、芥花油、棕榈油、橄榄油及myglyol,其中脂肪酸碳数在12至22之间,且其中脂肪酸可为饱和脂肪酸或不饱和脂肪酸。视情况带电脂质或磷脂悬浮于中性油中。适合的磷脂为(但不限于)磷脂酰丝胺酸,其以巨噬细胞上的受体为目标。本文提供的医药组成物视情况在水性介质中调配或使用已知技术调配为乳液。
本文提供的医药组成物可视情况包括别处描述的活性剂,及视情况存在的其它治疗成分。载剂及其它治疗成分必须在与组成物的其它成分兼容的意义上为可接受的且对其接受者无害。
医药组成物以有效抑制或减少癌细胞生长的量投予。所投予医药组成物的剂量将视所治疗病状的严重程度、特定调配物及其它临床因素(诸如接受者的体重及一般状态及投药途径)而定。
借由比较本文提供的医药组成物的试管内活性与动物模型中的活体内活性来测定本文提供的医药组成物的适用剂量。此项技术中已知将小鼠及其它动物中的有效剂量外推成人类有效剂量的方法;例如参看美国专利第4,938,949号,其以引用的方式并入本文中。
NPM抑制剂或抗癌剂可以任何有效量投予。在一些具体实例中,其可以约0.01μg至约5g、约0.1μg至约1g、约1μg至约 500mg、约10μg至约100mg、约50μg至约50mg、约100μg 至约10mg、约0.5μg至约5μg、约15μg至约500μg、约3μg 至约1mg、约7μg至约1mg、约10μg至约20μg、15μg至约 1mg、约15μg至约300μg、约15μg至约200μg、约15μg至约100μg、约15μg至约60μg、约15μg至约45μg、约30μg 至约60μg或约50μg至约100μg范围内的剂量投予。在某些具体实例中,NPM抑制剂或抗癌剂以每公斤体重约0.1μg至每公斤体重约200mg、每公斤体重约1μg至每公斤体重约100mg、每公斤体重约100μg至每公斤体重约50mg、每公斤体重约0.5mg 至每公斤体重约20mg、每公斤体重约1mg至每公斤体重约10mg、每公斤体重约10μg至每公斤体重约200μg、每公斤体重至少约 0.01μg、每公斤体重约0.1μg或每公斤体重至少约0.5μg的范围内的剂量投予。
根据本文提供的方法,借由多种途径中的任一者传递医药组成物,包括(但不限于)注射(例如皮下、肌肉内、静脉内、动脉内、腹膜内、皮内);皮肤;真皮;经皮;经口(例如锭剂、药丸、药液、可食用膜带);植入渗透泵;栓剂;气溶胶喷雾;局部;关节内;经眼;鼻吸入;肺吸入;压入皮肤及阴道中。
医药组成物可以单个剂量处理或多个剂量处理经适于所治疗病状的时间段投予。医药组成物宜以适当时间间隔投予,例如每天一次、每天两次、每天三次、每两天一次、每三天一次或每周一次、经至少3个月的时间段或直至病状的症状或征象消退。
抑制癌症生长的方法
本发明的一些具体实例是针对抑制个体中癌症生长的方法,其包含向有需要的个体投予有效量的至少一种NPM抑制剂及至少一种抗癌剂(如本文所述),借此减轻该个体的癌症的症状及 /或征象。
核仁磷酸蛋白或NPM(SEQ ID NO:1)为在细胞周期期间在核仁与细胞质之间穿梭的高度保守抗细胞凋亡蛋白。在正常条件下,NPM位于核仁中,但少量存在于核质中(图1B,左)。BCL2 相关X蛋白(BAX),即线粒体介导的细胞凋亡蛋白,主要位于核质中,但少量存在于细胞溶质中(图1C,左)。
回应于细胞应力(例如UV辐射或与抗癌剂接触),NPM自核仁移位至核质(图1B,中间图)及细胞溶质(图1B,右图),且结合于BAX。在不受任何特定理论约束的情况下,咸信细胞溶质中NPM与BAX的结合有效阻断BAX的线粒体移位、寡聚及活化,从而使得细胞抗细胞死亡(参看图2中的死亡逃避路径)。
借由抑制NPM表现,细胞溶质BAX移位至线粒体且以BAX 发生寡聚的线粒体内膜为目标。线粒体形成孔,失去膜电位,向细胞质中释放细胞色素C,且活化细胞凋亡级联(参看图2中的细胞凋亡路径)。
本发明组成物及方法可用于治疗或抑制任何类型的癌症生长。在一些具体实例中,待治疗癌症或待抑制的癌症生长为实体肿瘤或血液肿瘤,诸如肝癌、胆管癌、乳癌、肺癌、胃癌、胰脏癌、结肠直肠癌、子宫癌、子宫颈癌、白血病及淋巴瘤。
治疗可单独投予,或作为手术的辅助手段投予,例如在手术前减小肿瘤尺寸及/或在手术后降低转移可能性,例如借由抑制循环肿瘤细胞的生长及经由血流迁移。
NPM抑制剂可在抗癌剂之前、之后或与其同时投予。
在某些情形下,疗法包括与NPM抑制剂一起投予的抗癌剂组合。
以下实例进一步说明本发明。此等实例仅欲说明本发明且不解释为限制。
材料与方法
1.制备癌细胞、NPM表现抑制剂及转染
人类肝癌(HCC)细胞是、HepG2(野生型p53)、Hep3B(空白基因型p53)、Huh7(C200Y突变型p53)、Mahlavu(S249R 突变p53)、结肠直肠癌细胞是HCT-116、卵巢癌细胞是SKOV3及MDAH2774、肺癌细胞是A549、子宫颈癌细胞是HeLa及乳癌细胞是MCF7自美国菌种保存中心(American Type Culture Collection)(Manassas,VA)获得。胃癌细胞是TSGH购自University of California,San Francisco(San Francisco,CA),胆管癌细胞是HuCCT-1购自JCRB细胞库且子宫癌细胞是Ishikawa 购自Sigma-Aldrich(Switzerland)。
以NPM(参看SEQ ID NO:2-5)及p53(siTP53)为目标的预先设计的小干扰RNA(siRNA),及具有错义序列的siRNA(siNS) 购自Ambion,Austin,TX。详言之,研究中所用的siNM为选择阴性对照组#1。如Hsieh等人,“Identifying apoptosis-evasionproteins/pathways in human hepatoma cells via induction of cellular hormesisby UV irradiation.”J Proteome Res 2009;8:3977-3986中先前所述进行转染。
NPM抑制剂NSC348884购自SantaCruz Biotechnology(Santa Cruz,CA)且藤黄酸购自Enzo Life Siences(Farmingdale,NY)。
2.UV照射、药物处理及细胞存活/生存力分析
在实施例1中,将1×104个癌细胞接种于96孔板的各孔中,随后以实施例1中的siRNA转染。转染后48小时,以(50mJ/cm2) UV-B(290-320nm)或以下化学治疗剂中的一者处理90%汇合的细胞:丝裂霉素C(Kyowa Hakko Kogyo有限公司)、顺铂(Bristol-MyersSquibb公司)或小红莓(Pfizer Italia公司)。在DMSO中制备诸如索拉非尼(由BayerHealthCare,German友好提供)及拉帕替尼(购自GlaxoSmithKline plc)的目标癌症疗法。在各实验中,向未经处理的HCC细胞中添加溶剂作为对照组。在处理后24小时至48小时评定细胞生存力。
对于UV照射组,在曝露于30、65或100mJ/cm2 UV-B之后 24小时借由XTT分析(Roche Applied Science,Mannheim, Germany)测定细胞生存力/存活。实验一式三份至少重复进行两次,且使用各剂量的平均值计算一半最大抑制剂浓度(IC50)。
在实施例6中,将2×104个癌细胞接种于24孔板的各孔中,培养隔夜,随后进行组合药物处理。在曝露72小时后评定IC50、 IC90、细胞生存力及组合指数。
3.原位邻位连接分析及免疫共沉淀
使用抗NPM小鼠单克隆抗体及抗BAX兔多株抗体或抗肌动蛋白兔多株抗体(阴性对照组)作为一级抗体且使用与短的互补 DNA链偶合的抗小鼠及抗兔抗体作为二级抗体。在NPM与BAX 之间直接接触的情形下连接DNA链与环形寡聚物,且随后根据制造商说明使用Duolink II套组(Olink Bioscience,Uppsala,SWE) 进行滚环扩增并入经标记核苷酸。在洗涤且以DAPI(4',6-二甲脒基-2-苯基吲哚,用于DNA的荧光染色剂)对比染色后,安装载片且在荧光显微镜下检测。
使细胞在10cm板中生长用于免疫共沉淀(co-IP)。添加500 μl co-IP溶胞缓冲液(50mM Tris-HCl、150mM NaCl、1mM EDTA、 1%TritonX-100(pH 7.4)、1mM PMSF、1mMNa3VO4、1μg/ml 抑肽酶),同时将培养皿置于冰上。刮落细胞,接着借由在冰上温和摇动15分钟而溶胞。将细胞溶胞产物在12000g下在4℃下离心5分钟以移除碎片。将上清液收集于新鲜试管中,且添加2μg 针对NPM或BAX的第一抗体。在4℃下温和摇动反应混合物隔夜,且随后添加20μl 50%蛋白A-琼脂糖凝胶珠粒浆液。在4℃下培育所得混合物2小时,随后在6000g下在4℃下离心5分钟。保留上清液作为IP效率对照组,同时用缓冲液(10mM Tris-HCl、 500mM NaCl(pH 7.4))洗涤珠粒3次,且在95℃下在50μl 2×SDS 加样缓冲液中加热10分钟,随后以如上文所述的经识别抗体进行免疫墨点分析。
4.患者及组织样品
台湾长庚纪念医院医学伦理学内部审查委员会(Internal Review Board forMedical Ethics of Chang Gung Memorial Hospital in Taiwan)批准试样收集程序。来自90位HCC患者的HCC及其周围组织以及相关临床数据获自台湾肝癌网(Taiwan LiverCancer Network,TLCN)。检验所有HCC组织且选择来自最具代表性区域的两个核样品用于组织微数组块。自各HCC组织的不同区域选择两个核样品。
由两个独立观察者测定免疫组织化学 (ImmunoHistoChemistry,IHC)评分。若两个观察者之间存在意见不一致,则对载片进行再检验且观察者达成一致。IHS评分0 指示阴性结果,1指示弱阳性结果,2指示阳性结果且3指示强阳性结果。
使用T.C.Chou:Theoretical Basis,Experimental Design, and ComputerizedSimulation of Synergism and Antagonism in Drug Combination Studies,Pharmacological Reviews.2006; 58(3):621-81的方法分析药物的组合结果且以组合指数(CI)表示,该文献的全部揭示内容以引用的方式并入本文中。在0.3-0.7 之间的CI指示协同作用,0.7-0.85指示中等协同作用,0.85-0.9 指示微小协同作用,0.9-1.1指示累加作用,1.1-1.2指示微小拮抗作用,1.2-1.45指示中等拮抗作用且1.45-3.3指示拮抗作用。
如美国癌症联合委员会/国际抗癌联盟(American Joint Committee on Cancer/International Union A gainst Cancer)所建议,根据肿瘤-结节-转移(tumor-node-metastasis,TNM)分期系统判断肿瘤分期。
使用卡方检验(Chi-square test)及费雪精准检验(Fishers Exact test)比较变量。使用卡普兰-迈耶分析(Kaplan-Meier analysis)及对数等级测试(log-rank test)说明患者接受初步治愈性肝切除术后无复发及整体存活几率。
实施例1:HCC中NPM抑制剂及抗癌剂组合的试管内评估
此研究中使用具有不同p53背景的HCC细胞是,包括HepG2 (野生型p53)、Huh7(C200Y突变型p53)、Mahlavu(R249S 突变型p53)及Hep3B(缺失型p53)。
参看图3,0mJ/cm2或mg/ml剂量的UVB、MMC、DOXO及 CODP指示HCC细胞未经UV-B或已知化学治疗剂处理。siNPM (抑制NPM表现的siRNA)柱表示无UV-B或化学治疗剂处理但具有NPM抑制的群组。siNS柱表示无UV-B、化学治疗剂处理或 NPM抑制的群组。借由免疫墨点法确认siNPM对NPM表现的抑制(图3,右下图)。
当UVB、MMC、DOXO及CODP的剂量高于0mJ/cm2或μg/ml 时,以UV-B或已知化学治疗剂中之一者处理HCC细胞。在此群组中,siNs柱表示无NPM表现抑制,但经UV-B或已知化学治疗剂处理的群组。siNPM柱群组具有NPM抑制且经化学治疗剂或 UV-B辐射处理。借由XTT分析量测细胞生存力。*(p<0.05) 及**(p<0.01)指示经siNPM及siNS转染的细胞之间的统计显著性。
NPM表现抑制与化学疗法或UV-B处理的组合相较于单独 NPM表现抑制显著降低HCC细胞的细胞生存力。结果显示NPM 表现抑制与化学疗法或UV-B处理的组合在HCC处理中有效。
参看图7,0μM或nM剂量的索拉非尼及拉帕替尼指示HCC 细胞未经目标癌症疗法处理。在0μM或nM下,siNS(黑色)柱表示无NPM表现抑制及无目标癌症疗法(对照组),而siNPM(灰色)柱表示具有NPM表现抑制,但无目标癌症疗法的群组。
高于0μM或nM的剂量的索拉非尼及拉帕替尼指示HCC细胞经目标癌症疗法处理。索拉非尼及拉帕替尼剂量高于0μM或 nM的siNS(黑色)柱表示无NPM表现抑制,但经目标癌症疗法处理的群组,而索拉非尼及拉帕替尼剂量高于0μM或nM的 siNPM(灰色)柱表示具有NPM表现抑制且经目标癌症疗法处理的群组。
抑制NPM表现与目标癌症疗法的组合相较于单独NPM表现抑制或目标癌症疗法显著提高Huh7、Hep3B及Mahlavu细胞的细胞易感性。结果显示NPM表现抑制与目标癌症疗法的组合在HCC 处理中提供协同作用。
进一步评估由癌细胞中的NPM配合的p53在死亡逃避中的作用。NPM、p53或同时NPM与p53的表现因siNPM及siTP53而沉默(图4)。单独p53表现的沉默不会显著改变Huh7、Hep3B及Mahlavu细胞中的处理敏感性(图4,siTP53相对于siNS)。 p53与NPM的同时沉默不会进一步改变单独沉默NPM所发挥的致敏作用[图4,siNPM/siNS相对于(siNPM+siTP53)/siNS]。NPM 表观上独立于p53实现其死亡逃避活性。此等发现具有极大临床意义,因为一半以上人类癌症(包括HCC,尤其为晚期HCC)中发现了p53突变。
实施例2:细胞应力对NPM及BAX表现的诱导
现参看图1A,在UV-B(50mJ/cm2)、顺铂[对于Hep3B(3B)、 HepG2(G2)及Mahlavu(ML)分别为5.5、69及6.4μg/ml]及小红莓[对于Hep3B、HepG2及Mahlavu分别为1.4、8.8及5μg/ml] 曝露后,Huh7、Hep3B及Mahlavu细胞中的NPM上调。在UV-B、顺铂及小红莓处理后,所有三种HCC细胞是中的BAX表现亦增加。使用β激动蛋白的表现作为加样对照组。在细胞应力下同时诱导细胞的BAX(促细胞凋亡)及NPM(抗细胞凋亡)表示调节细胞凋亡相对于存活反应的抵消机制。
实施例3:在细胞应力后NPM的核质及细胞质移位
在UV照射之前,NPM主要位于核仁中且少量存在于核质中 (图1B,左图),而BAX主要位于核质中且少量位于细胞质中 (图1C,左图)。在UV照射后,NPM自核仁移位至核质(图1B,中间)及细胞质(图1B,右图,由箭头指示)。另一方面,BAX移位至细胞溶质且在线粒体中累积,在细胞经历细胞凋亡时尤其如此(图1C,右图;由箭头指示)。
在由siRNA抑制NPM表现后,具有相对低NPM表现的HCC 细胞在线粒体中聚集较多BAX,且发现更倾向于细胞凋亡,而具有相对高NPM含量的细胞具有较少线粒体BAX累积,且发现对细胞凋亡更具抗性。此等发现表明NPM的抗细胞凋亡活性涉及阻断BAX线粒体移位。
实施例4:由NPM阻断BAX线粒体移位及寡聚
图6A说明在UV照射后细胞质NPM增加,而在UV照射后细胞溶质及线粒体中的BAX增加。由siRNA抑制NPM表现会减少细胞溶质BAX,而线粒体BAX含量会增加。此表明响应于细胞应力(诸如UV处理)由NPM阻断BAX线粒体移位。分别使用抗增殖蛋白(prohibitin,PHB)及甘油醛3-磷酸去氢酶 (glyceraldehyde 3-phosphate dehydrogenase,GAPDH)作为线粒体及细胞溶质组分的标记。借由在Hep3B及Mahlavu细胞中以化学治疗剂(诸如星形孢菌素(staurosporin))抑制NPM来观察线粒体BAX提高的类似结果。
采用制备细胞蛋白质的非还原条件验证上述发现。抑制NPM 表现(图6B,泳道2)在UV照射后大大增加线粒体BAX的二聚物及寡聚物,而在UV照射前(图6B,泳道1)或在无NPM表现抑制情况下(图6B,泳道3)仅在线粒体中检测到BAX二聚物及寡聚物。总之,NPM阻断HCC细胞中BAX的线粒体移位及寡聚。
实施例5:人类HCC中的NPM上调与B型肝炎、门静脉受侵、高复发及不良预后相关
使用免疫墨点分析法,发现相较于匹配的副HCC肝组织及正常肝组织,在6个HCC样品的4个中NPM含量高(图5)。
检验90对HCC及副HCC肝样品中的NPM表现。在38.9% (35/90)的HCC样品中发现NPM过表现,且与慢性B型肝炎(p <0.0001)、晚期癌症阶段(p=0.0015)、门静脉受侵(p<0.001)、肿瘤复发(p=0.0148)及不良整体存活(p=0.0229)强相关。参看表1-4。如经由卡普兰-迈耶分析及对数等级测试所证明,NPM 上调与较高肿瘤复发及较低整体存活相关。
表1.HCC患者的NPM表现与临床表现的相互关系
表2. 45对B型肝炎相关HCC及非-HCC肝组织在组织数组上的NPM表现的免疫组织化学评分。
IHC评分0 | IHC评分1 | IHC评分2 | IHC评分3 | 小计 | |
I期 | 6 | 5 | 2 | 2 | 15 |
II期 | 9 | 0 | 6 | 0 | 15 |
III期 | 3 | 5 | 1 | 6 | 15 |
小计 | 18 | 10 | 9 | 8 | 45 |
表3. 45对C型肝炎相关HCC及非-HCC肝组织在组织数组上的NPM表现的免疫组织化学评分。
IHC评分0 | IHC评分1 | IHC评分2 | IHC评分3 | 小计 | |
I期 | 11 | 3 | 1 | 0 | 15 |
II期 | 12 | 0 | 2 | 1 | 15 |
III期 | 14 | 1 | 0 | 0 | 15 |
小计 | 37 | 4 | 3 | 1 | 45 |
表4.HCC患者的NPM表现与临床表现的关系
HBV=慢性B型肝炎;HCV=慢性C型肝炎;a克拉斯卡-瓦立斯测试 (Kruskal-Wallis test);b史皮尔曼相关(Spearman correlation)=0.229;c对数等级测试。
实施例6:多种癌症细胞是中NPM抑制剂及抗癌剂组合的试管内评估
在以下癌症细胞是中评估NPM抑制剂与抗癌剂的组合:HCC 细胞是(Huh7及Mahlavu)、胃癌细胞是(TSGH)、胆管癌细胞是(HuCCT-1)、结肠直肠癌细胞是(HCT-116)、卵巢癌细胞是(SKOV3及MDAH2774)、肺癌细胞(A549)、子宫癌细胞是(Ishikawa)、子宫颈癌细胞是(HeLa)及乳癌细胞是(MCF7)。
如表5中所示,索拉非尼(抗癌剂)及NPM抑制剂(NSC348884 或藤黄酸)组合对HCC细胞系的整体作用指示累加作用至协同作用。
表5.索拉非尼与NSC348884或藤黄酸的组合对HCC的作用。
表6中总结拉帕替尼(抗癌剂)与藤黄酸(NPM抑制剂)组合对8种不同癌症细胞系的作用。整体而言,所有癌症细胞系的结果均指示累加作用至协同作用。
表6.拉帕替尼与藤黄酸的组合对多种癌症细胞系的作用。
表7中总结拉帕替尼(抗癌剂)与NSC348884(NPM抑制剂) 组合对8种不同癌症细胞系的作用。整体而言,所有癌症细胞系的结果均指示混合的累加作用/协同作用。
表7.拉帕替尼与NSC348884的组合对多种癌症细胞系的作用。
此等结果证明拉帕替尼(抗癌剂)与NSC348884(NPM抑制剂)的组合处理在多数癌症细胞系中产生累加至协同抗癌作用,但Mahlavu(HCC)及HeLa(子宫颈)细胞系除外。
参看表8,需要较低浓度的拉帕替尼及NSC348884抑制HCC 及子宫颈癌,其为组合疗法形式而非单一疗法形式。结果指示拉帕替尼及NSC348884组合在癌细胞抑制方面有效且可以小于单一疗法方案中通常投予的剂量的剂量存在。
表8.拉帕替尼及NSC348884作为单一疗法及组合疗法在HCC 及子宫颈癌细胞中的IC50。
Claims (3)
1.一种医药组成物,其包含:
至少一种NPM抑制剂,该NPM抑制剂为藤黄酸;
至少一种抗癌剂,该抗癌剂为索拉非尼或拉帕替尼;及
医药学上可接受的载剂。
2.藤黄酸和激酶抑制剂在制备减少或抑制个体中癌症生长的药物中的用途,其中该癌症选自于肝癌、胃癌、胆管癌、结肠直肠癌、卵巢癌、肺癌、子宫癌或乳癌,并且该激酶抑制剂为索拉非尼或拉帕替尼。
3.抑制NPM表现的siRNA和激酶抑制剂在制备减少或抑制个体中癌症生长的药物中的用途,其中该癌症选自于p53突变型或p53缺失型肝细胞肝癌,其中该抑制NPM表现的siRNA如SEQ ID:2-5所示,并且该激酶抑制剂为索拉非尼或拉帕替尼。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261700756P | 2012-09-13 | 2012-09-13 | |
US61/700,756 | 2012-09-13 | ||
PCT/US2013/059723 WO2014043510A1 (en) | 2012-09-13 | 2013-09-13 | A novel pharmaceutical composition and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105744958A CN105744958A (zh) | 2016-07-06 |
CN105744958B true CN105744958B (zh) | 2019-11-05 |
Family
ID=50278719
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380047401.6A Expired - Fee Related CN105744958B (zh) | 2012-09-13 | 2013-09-13 | 新颖医药组成物及其用途 |
Country Status (4)
Country | Link |
---|---|
US (2) | US9592407B2 (zh) |
CN (1) | CN105744958B (zh) |
TW (1) | TWI614029B (zh) |
WO (1) | WO2014043510A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102664243B1 (ko) * | 2018-01-19 | 2024-05-08 | 데루타-후라이 화마 가부시키가이샤 | 암 환자의 치료에 유용한 오줌의 알칼리제 |
CN110716042A (zh) * | 2019-10-23 | 2020-01-21 | 郑州大学 | 一种用于卵巢癌早期筛查和诊断的血清蛋白标志物、试剂盒及检测方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4938949A (en) | 1988-09-12 | 1990-07-03 | University Of New York | Treatment of damaged bone marrow and dosage units therefor |
US8063089B2 (en) * | 2007-02-28 | 2011-11-22 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Inhibitors of nucleophosmin (NPM) and methods for inducing apoptosis |
WO2010056735A1 (en) * | 2008-11-11 | 2010-05-20 | The Trustees Of The University Of Pennsylvania | Compositions and methods for inhibiting an oncogenic protein to enhance immunogenicity |
US20120208755A1 (en) * | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
-
2013
- 2013-09-13 WO PCT/US2013/059723 patent/WO2014043510A1/en active Application Filing
- 2013-09-13 US US14/427,772 patent/US9592407B2/en active Active
- 2013-09-13 TW TW102133188A patent/TWI614029B/zh active
- 2013-09-13 CN CN201380047401.6A patent/CN105744958B/zh not_active Expired - Fee Related
-
2017
- 2017-01-19 US US15/410,307 patent/US9901594B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US20170136053A1 (en) | 2017-05-18 |
TW201446266A (zh) | 2014-12-16 |
US9901594B2 (en) | 2018-02-27 |
CN105744958A (zh) | 2016-07-06 |
TWI614029B (zh) | 2018-02-11 |
US20150224334A1 (en) | 2015-08-13 |
WO2014043510A1 (en) | 2014-03-20 |
US9592407B2 (en) | 2017-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Efferth | From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy | |
Bauerschlag et al. | Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer | |
Cao et al. | Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts | |
RU2480211C2 (ru) | Лечение рака молочной железы с помощью соединения 4-иод-3-нитробензамид в комбинации с противоопухолевыми средствами | |
JP5688288B2 (ja) | がんの処置のための相乗的な医薬の組合せ | |
Hoda et al. | Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy | |
Ma et al. | Enhanced immunotherapy of SM5-1 in hepatocellular carcinoma by conjugating with gold nanoparticles and its in vivo bioluminescence tomographic evaluation | |
WO2009064444A2 (en) | Treatment of uterine cancer and ovarian cancer with a parp inhibitor alone or in combination with anti-tumor agents | |
Wen et al. | Effect of Y6, an epigallocatechin gallate derivative, on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells | |
EP1796688A1 (en) | Pancreatic cancer treatment using na+/k+ atpase inhibitors | |
Jia et al. | Effect of bevacizumab on the tight junction proteins of vascular endothelial cells | |
Lv et al. | Nanosized drug delivery systems for breast cancer stem cell targeting | |
Peng et al. | AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway | |
CN105744958B (zh) | 新颖医药组成物及其用途 | |
Yang et al. | Isorhamnetin induces cell cycle arrest and apoptosis by triggering DNA damage and regulating the AMPK/mTOR/p70S6K signaling pathway in doxorubicin-resistant breast cancer | |
Ashique et al. | Multi drug resistance in colorectal cancer-approaches to overcome, advancements and future success | |
Wang et al. | A highly integrated precision nanomedicine strategy to target esophageal squamous cell cancer molecularly and physically | |
Wen et al. | Effect of | |
Soares et al. | The combination of Cl-IB-MECA with paclitaxel: A new anti-metastatic therapeutic strategy for melanoma | |
Jin et al. | Anti-hepatocarcinoma effects of 5-fluorouracil encapsulated by galactosylceramide liposomes in vivo and in vitro | |
Liu et al. | Oridonin enhances the anti-tumor activity of gemcitabine towards pancreatic cancer by stimulating Bax-and Smac-dependent apoptosis | |
Oshita et al. | Comparison of nedaplatin and irinotecan for patients with squamous and nonsquamous cell carcinoma of the lung: meta-analysis of four trials | |
Loilome et al. | Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma | |
TW201717926A (zh) | 用於治療尤文氏家族腫瘤(ewing family tumors)的組成物及方法 | |
RU2551238C2 (ru) | Способ индукции апоптоза клеток злокачественной опухоли колоректального рака и средство для его осуществления |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191105 Termination date: 20210913 |