WO2014094178A1 - Radiosensitizer compounds for use in combination with radiation - Google Patents
Radiosensitizer compounds for use in combination with radiation Download PDFInfo
- Publication number
- WO2014094178A1 WO2014094178A1 PCT/CA2013/051005 CA2013051005W WO2014094178A1 WO 2014094178 A1 WO2014094178 A1 WO 2014094178A1 CA 2013051005 W CA2013051005 W CA 2013051005W WO 2014094178 A1 WO2014094178 A1 WO 2014094178A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- cancer
- ring
- radiation
- alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 337
- 239000002534 radiation-sensitizing agent Substances 0.000 title claims abstract description 111
- 230000005855 radiation Effects 0.000 title claims description 65
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 171
- 201000011510 cancer Diseases 0.000 claims abstract description 126
- 238000011282 treatment Methods 0.000 claims abstract description 92
- 238000001959 radiotherapy Methods 0.000 claims abstract description 84
- 230000027756 respiratory electron transport chain Effects 0.000 claims abstract description 64
- 125000003118 aryl group Chemical group 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 47
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 35
- 150000002367 halogens Chemical class 0.000 claims abstract description 35
- 238000002648 combination therapy Methods 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 210000004027 cell Anatomy 0.000 claims description 213
- 230000005865 ionizing radiation Effects 0.000 claims description 105
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 125000000304 alkynyl group Chemical group 0.000 claims description 52
- 125000003342 alkenyl group Chemical group 0.000 claims description 50
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
- 230000000694 effects Effects 0.000 claims description 43
- -1 cycloalkynyl Chemical group 0.000 claims description 42
- 239000003814 drug Substances 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 24
- 230000001093 anti-cancer Effects 0.000 claims description 21
- 125000006413 ring segment Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- 210000004881 tumor cell Anatomy 0.000 claims description 13
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 230000002708 enhancing effect Effects 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 150000001721 carbon Chemical class 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 230000002147 killing effect Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 239000011885 synergistic combination Substances 0.000 abstract description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 61
- 229960004316 cisplatin Drugs 0.000 description 60
- 230000004083 survival effect Effects 0.000 description 36
- 241000699670 Mus sp. Species 0.000 description 32
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 31
- 230000001988 toxicity Effects 0.000 description 27
- 231100000419 toxicity Toxicity 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- 230000000637 radiosensitizating effect Effects 0.000 description 26
- 231100000331 toxic Toxicity 0.000 description 22
- 230000002588 toxic effect Effects 0.000 description 22
- 231100000002 MTT assay Toxicity 0.000 description 21
- 238000000134 MTT assay Methods 0.000 description 21
- 239000002246 antineoplastic agent Substances 0.000 description 21
- 238000000338 in vitro Methods 0.000 description 21
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 19
- 108020004414 DNA Proteins 0.000 description 19
- 239000012091 fetal bovine serum Substances 0.000 description 19
- 230000035899 viability Effects 0.000 description 19
- 239000002609 medium Substances 0.000 description 17
- 238000007912 intraperitoneal administration Methods 0.000 description 16
- 229910001868 water Inorganic materials 0.000 description 16
- 206010008342 Cervix carcinoma Diseases 0.000 description 15
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 15
- 201000010881 cervical cancer Diseases 0.000 description 15
- 230000002354 daily effect Effects 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 13
- 229940126062 Compound A Drugs 0.000 description 13
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 238000001727 in vivo Methods 0.000 description 13
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 12
- 230000003833 cell viability Effects 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 230000006378 damage Effects 0.000 description 11
- 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 10
- 241001465754 Metazoa Species 0.000 description 10
- 238000011579 SCID mouse model Methods 0.000 description 10
- 230000007059 acute toxicity Effects 0.000 description 10
- 231100000403 acute toxicity Toxicity 0.000 description 10
- 229960004716 idoxuridine Drugs 0.000 description 10
- 231100000956 nontoxicity Toxicity 0.000 description 10
- 229910052697 platinum Inorganic materials 0.000 description 10
- 230000005778 DNA damage Effects 0.000 description 9
- 231100000277 DNA damage Toxicity 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 9
- 239000011550 stock solution Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 8
- 206010070863 Toxicity to various agents Diseases 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000003792 electrolyte Substances 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 8
- 231100000252 nontoxic Toxicity 0.000 description 8
- 230000003000 nontoxic effect Effects 0.000 description 8
- 238000007911 parenteral administration Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 206010033128 Ovarian cancer Diseases 0.000 description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 description 7
- 230000005782 double-strand break Effects 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 7
- 238000003608 radiolysis reaction Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000007928 intraperitoneal injection Substances 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 229940056360 penicillin g Drugs 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 125000003367 polycyclic group Chemical group 0.000 description 6
- CAFSXVAFGILCCI-UHFFFAOYSA-N pyrazine-2,3-diamine Chemical compound NC1=NC=CN=C1N CAFSXVAFGILCCI-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229960005322 streptomycin Drugs 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 238000000246 agarose gel electrophoresis Methods 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229940044683 chemotherapy drug Drugs 0.000 description 5
- 208000014829 head and neck neoplasm Diseases 0.000 description 5
- 231100000304 hepatotoxicity Toxicity 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 5
- 231100000417 nephrotoxicity Toxicity 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 230000002195 synergetic effect Effects 0.000 description 5
- UWXPRSOEIMNKQW-UHFFFAOYSA-N 1-N,2-N-dibromobenzene-1,2-diamine Chemical compound BrNC1=C(C=CC=C1)NBr UWXPRSOEIMNKQW-UHFFFAOYSA-N 0.000 description 4
- JIVQZEYXNZTAEM-UHFFFAOYSA-N 3,4-dibromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C(Br)=C1N JIVQZEYXNZTAEM-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 231100001092 no hepatotoxicity Toxicity 0.000 description 4
- 231100001095 no nephrotoxicity Toxicity 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000011127 radiochemotherapy Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 229910021642 ultra pure water Inorganic materials 0.000 description 4
- 239000012498 ultrapure water Substances 0.000 description 4
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 3
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 3
- PBVBFKPJZFNFNY-UHFFFAOYSA-N 3,4-dichlorobenzene-1,2-diamine Chemical compound NC1=CC=C(Cl)C(Cl)=C1N PBVBFKPJZFNFNY-UHFFFAOYSA-N 0.000 description 3
- WJLQWHVSEONCRS-UHFFFAOYSA-N 3,4-diiodobenzene-1,2-diamine Chemical compound NC1=CC=C(I)C(I)=C1N WJLQWHVSEONCRS-UHFFFAOYSA-N 0.000 description 3
- VWYTZNPMXYCBPK-UHFFFAOYSA-N 3-bromobenzene-1,2-diamine Chemical compound NC1=CC=CC(Br)=C1N VWYTZNPMXYCBPK-UHFFFAOYSA-N 0.000 description 3
- 206010019851 Hepatotoxicity Diseases 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 206010029155 Nephropathy toxic Diseases 0.000 description 3
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000011543 agarose gel Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000005880 cancer cell killing Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940109239 creatinine Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000013480 data collection Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000009650 gentamicin protection assay Methods 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 230000007686 hepatotoxicity Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 231100001231 less toxic Toxicity 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 230000007694 nephrotoxicity Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 210000003752 saphenous vein Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 2
- 208000012766 Growth delay Diseases 0.000 description 2
- 208000034970 Heterotopic Ossification Diseases 0.000 description 2
- 206010023330 Keloid scar Diseases 0.000 description 2
- 206010024264 Lethargy Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 201000002154 Pterygium Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 201000008754 Tenosynovial giant cell tumor Diseases 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 208000004064 acoustic neuroma Diseases 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000009702 cancer cell proliferation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 238000009643 clonogenic assay Methods 0.000 description 2
- 231100000096 clonogenic assay Toxicity 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 208000035647 diffuse type tenosynovial giant cell tumor Diseases 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005021 gait Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 150000005694 halopyrimidines Chemical class 0.000 description 2
- 230000007941 heterotopic ossification Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000001307 laser spectroscopy Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 208000026037 malignant tumor of neck Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 231100000324 minimal toxicity Toxicity 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 208000007420 pigmented villonodular synovitis Diseases 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000002628 unsealed source radiotherapy Methods 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000012447 xenograft mouse model Methods 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- AXDGIPMYJALRKV-UHFFFAOYSA-N 2-iodopyrimidine Chemical compound IC1=NC=CC=N1 AXDGIPMYJALRKV-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OCYROESYHWUPBP-CIUDSAMLSA-N Pro-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)[C@@H]1CCC[NH2+]1 OCYROESYHWUPBP-CIUDSAMLSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 150000001298 alcohols Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 208000034404 cisplatin toxicity Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 150000001983 dialkylethers Chemical group 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002485 inorganic esters Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 150000002823 nitrates Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000002409 penten-3-yl group Chemical group C=CC(CC)* 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical group 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 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
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108010015796 prolylisoleucine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 201000011096 spinal cancer Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000014618 spinal cord cancer Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000002942 systemic radioisotope therapy Methods 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000003462 vein Anatomy 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
- 229960004528 vincristine Drugs 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
Definitions
- Cancer is a major health problem across the globe. Current treatments generally involve surgery, radiation therapy (radiotherapy), chemotherapy, or a combination of these approaches, each of which has limitations. There remains a need for new and improved cancer therapies, including combination therapies.
- Radiotherapy involves the application of ionizing radiation as part of a treatment to control or kill malignant cells.
- Ionizing radiation is used to damage the DNA of exposed tissue leading to cell death.
- Radiotherapy may be curative in a number of types of cancer. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgical removal. Radiotherapy may be synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. Many common cancer types can be treated with radiation therapy in some way. The precise treatment intent will depend on the tumor type, location, stage, and health of the patient.
- Radiotherapy also has applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification.
- the direct action of radiation e.g. direct energy deposited in the DNA, accounts for only a small fraction of the energy deposited into the biological system.
- the cell contains 70-80% water. It is known that the contribution of free radicals, via radiolysis of water, to biological damage far exceeds that of direct action in ionizing radiation, by orders of magnitude.
- Radiosensitivity The response of a cancer to radiation is described by its radiosensitivity. Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation. These include leukemias, most lymphomas and germ cell tumors. Most of the epithelial cancers are only moderately radiosensitive, and require a significantly higher dose of radiation (60-70 Gy) to achieve a radical cure. Some types of cancer, such as renal cell cancer and melanoma, are highly radioresistant and cannot be cured by radiation doses that are safe in clinical practice.
- the response of a tumor to radiotherapy is also related to its size and conditions. For complex reasons, very large tumors respond less well to radiation than smaller tumors or microscopic disease.
- One technique to enhance the radiosensitivity of a cancer is by giving a radiosensitizing drug (a so-called "radiosensitizer”) during a course of radiotherapy.
- Radiotherapy itself is painless, but it can cause serious side effects. Particularly high doses can cause varying side effects, including acute side effects happening in the months following treatment, long-term side effects in years following treatment, and cumulative side effects after re-treatment.
- the nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and the patient.
- Acute side effects include fatigue and skin irritation, nausea and vomiting, damage to the epithelial surfaces, mouth, throat and stomach sores, intestinal discomfort, swelling (edema) and infertility.
- efforts are made to use low radiation doses to reduce toxic side effects, e.g., by use of a radiosensitizer to enhance the treatment efficacy.
- Cisplatin (cz ' s-Pt( H3) 2 Cl 2 ) is a platinum-based antineoplastic drug and is one of the most widely used drugs for cancer treatment. Cisplatin has also been used as a radiosensitizer to enhance the radiosensitivity of the cancer during radiotherapy [Rose et al., 1999]. Despite its widespread use, cisplatin has two major drawbacks: severe toxic side effects and both intrinsic and acquired resistance. These drawbacks even led to the calling of terminating the clinical applications of the heavy-metal Pt-based anticancer drugs [Reese, 1995]. There remains a need to identify less toxic analogues and to develop combination therapies, including chemo-radiotherapies, that reduce cisplatin toxicity and prevent or overcome drug resistance.
- chemotherapeutic agents While a variety of chemotherapeutic agents have been combined with radiotherapy, nearly all are toxic. Chemotherapeutic agents generally cause significant, and often dangerous, side effects. Side effects associated with chemotherapeutic agents are generally the major factor in defining a dose-limiting toxicity (DLT) for the agent.
- DLT dose-limiting toxicity
- WO/2011/026219 entitled Combination Therapy for Cancer Comprising a Platinum-Based Antineoplastic Agent and a Biocompatible Electron Donor, there is disclosed a combination chemotherapy of cisplatin with an electron-donating agent to enhance the anti-cancer efficacy of cisplatin (also see, Lu, 2011).
- the present disclosure relates to non-platinum-based radiosensitizer compounds for use in combination with radiation therapy, e.g. to enhance radiotherapy.
- the present disclosure also relates to a combination therapy for cancer and other disorders treatable by radiation therapy.
- compositions, dosage forms, methods, uses, commercial packages and kits relating to the compounds are also disclosed herein.
- radiosensitizer compound useful in combination with radiation having the general formula I:
- A represents an aromatic core; at least one of R a and R b is an electron transfer promoter as defined herein; and at least one of R c is a leaving group as defined herein.
- the biocompatible radiosensitizer compound for use in combination with ionizing radiation has the general formula I: wherein A is a 5- or 6-membered aryl or heteroaryl ring containing 0-2 ring heteroatoms selected from the group consisting of N, O and S, the remaining ring atoms being carbon; R a and R b are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl or an electron transfer promoter, wherein at least one of R a and R b is an electron transfer promoter; R c is, independently for each occurrence, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl, or
- radiosensitizer compound having the general formula II:
- X and Y are independently C-R 3 or N;
- R 3 is H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl;
- R £ and R b are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, heteroaiyl or an electron transfer promoter, wherein at least one of R a and R b is an electron transfer promoter;
- R 1 and R 2 are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, hetero
- R 3 is H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, or heteroaiyl
- R 1 and R 2 are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, heteroaiyl, or a leaving group; wherein at least one of R 1 and R 2 is a leaving group, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl and heteroaiyl moieties is optional
- each of R a and R b is an electron transfer promoter.
- the electron transfer promoter is selected from the group consisting of -NH 2 , -NHR, -NR 2 , -OH, -NHCOCH3, -NHCOR, -OCH3, and - OR.
- the electron transfer promoter is -NH 2 , -NHR, or -NR 2 .
- R is substituted or unsubstituted alkyl.
- R a and R b are each electron transfer promotors.
- R a and R b are on adjacent ring carbon atoms.
- the electron transfer promoter is -NH 2 .
- the leaving group is halogen.
- the halogen is CI, Br or I.
- two R c groups on Ring A are halogen selected from the group consisting of CI, Br and I.
- Ring A is a 6-membered aryl or heteroaryl ring, such as, benzene, pyridine or pyrazine. In some embodiments Ring A is benzene.
- Ring A is benzene, pyridine or pyrazine; each of R a and R b are H 2 ; two R c substituents on Ring A are halogen each positioned meta to R a and R b on Ring A; and any remaining R c groups are as defined herein.
- Ring A is benzene and, in some further embodiments, the remaining carbons on Ring A are unsubstituted carbon.
- Ring A is pyridine and, in further embodiments, the remaining carbon on Ring A is unsubstituted.
- Ring A is pyrazine.
- R 1 and R 2 are both leaving groups, such as halogen.
- each halogen is selected from the group consisting of CI, Br and I.
- X and Y are C-R 3 .
- X is C-R 3 and Y is N.
- R 3 is H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaryl.
- R is H.
- X and Y are each N.
- the radiosensitizer compound is a compound selected from the group consisting of:
- the radiosensitizer compounds disclosed herein have an electron affinity greater than 0 eV. In some embodiments, the radiosensitizer compounds disclosed herein have an electron affinity between about +0.0 eV to +5 eV. In some embodiments, the radiosensitizer compounds disclosed herein have an electron affinity between about +0.5 eV and about +2.5 eV.
- radiosensitizer compounds as defined herein for enhancing the effects of radiation therapy in a subject receiving said radiation therapy.
- the subject is the receiving radiation therapy as a treatment for cancer.
- radiosensitizer compounds as defined herein for for use in the treatment of cancer in a subject receiving radiation therapy.
- radiosensitizer compounds as defined herein for for use in combination with radiation therapy in the treatment of cancer.
- radiosensitizer compounds as defined herein for for use in the manufacture of a medicament for the treatment of cancer in a subject receiving radi ati on therapy .
- radiosensitizer compounds as defined herein for use in the manufacture of a medicament for use in combination with radiation therapy the treatment of cancer.
- a radiosensitizer compound as defined herein to enhance radiation therapy in a subject receiving said radiation therapy.
- a radiosensitizer compound as defined herein in the treatment of cancer in a subject receiving radiation therapy.
- a radiosensitizer compound as defined herein in the manufacture of a medicament for the treatment of cancer in a subject receiving radi ati on therapy .
- a pharmaceutical composition for use in combination with ionizing radiation in the treatment of cancer comprising: an effective amount of a radiosensitizer compound as defined herein; and a pharmaceutically acceptable carrier or diluent.
- combination therapy for cancer comprising a radiosensitizer compound as defined herein and ionizing radiation.
- a method of enhancing radiotherapy in a subject in need thereof comprising: administering an effective amount of a radiosensitizer compound as defined herein to the subject in combination with an effective amount of ionizing radiation.
- method of providing an anti-cancer effect in a cancer cell comprising: a) administering to the cancer cell an effective amount of a radiosensitizer compound as defined herein; and b) administering to the cancer cell an effective amount of ionizing radiation, wherein a) and b) are administered sequentially or simultaneously to thereby provide the anti-cancer effect.
- the anticancer effect is killing of the cancer cell.
- the cancer cell is a tumour cell.
- a method of treating cancer in a subject in need thereof comprising: a) administering to the subject an effective amount of a radiosensitizer compound as defined herein; and b) administering to the subject an effective amount of ionizing radiation, wherein a) and b) are administered sequentially or simultaneously.
- the compound is administered before, during or after administration of the ionizing radiation.
- a method of treating cancer in a subject in need thereof comprising, administering to the subject a therapeutically effective amount of a radiosensitizer compound as defined herein before or simultaneously with an effective amount of ionizing radiation.
- kits comprising a radiosensitizer compound as defined herein; and instructions for use in combination with ionizing radiation.
- FIG. 1 Molecular structures of 12 exemplary radiosensitizer compounds: A: (4,5- )dichloro-(l,2-)diamino-benzene (4,5-dichloro-l,2-phenylenediamine); B: (4,5-)dibromo- (l,2-)diamino-benzene (4,5-dibromo-l,2-phenylenediamine); C: (4,5-)diiodo-(l,2-)diamino- benzene (4,5-diiodo-l,2-phenylenediamine); D: bromo-(l,2-)diamino-benzene; E: chloro- (l,2-)diamino-benzene; F: iodo-(l,2-)diamino-benzene; G: (4,5-)dichloro-(l,2-) diamino- pyrazine; H: (4,5-)di
- Figure 2 shows the DET reaction of the prehydrated electron (e pre ⁇ ) with an exemplary radiosensitizer (compound D), which was observed by fs-TRLS measurements.
- the results show femtosecond transient absorption kinetic trace of D* ⁇ /IdU* ⁇ resulting from the DET reaction of e pre ⁇ with compound D or iodopyrimidine (IdU) (e pre ⁇ + D/IdU ⁇
- D* IdU* ⁇ — » radical formation pumped at 322 nm and probed at 333 nm in fs-TRLS, showing that the DET reaction efficiency of compound D is much higher than that of IdU.
- e ⁇ pre was generated by two-UV photon excitation of water with the pump pulse.
- the probe pulse was used to monitor the formation and dissociation of D* IdU* ⁇ .
- Figure 3 illustrates the ionizing-radiation-induced damage to plasmid DNA in pure water and with 200 ⁇ Compound B.
- the damage was measured by agarose gel electrophoresis.
- Agarose gel electrophoresis images of the ionizing-radiation-induced damage to plasmid DNA in pure water and with 200 ⁇ Compound B, with various durations of a tiny electron source created by two-UV-photon excitation of water in the solution with the power indicated.
- SC supercoiled (undamaged DNA);
- SSB single-strand breaks; and
- DSB double-strand breaks. It is seen that Compound B induced significant enhancement of DSBs.
- Figure 4 illustrates the ionizing-radiation-induced damage to plasmid DNA in pure water and with 200 ⁇ Compound B. The damage was analyzed by agarose gel densitograms. Agarose gel densitograms for plasmid DNA in pure water, and 200 ⁇
- Figure 5 illustrates cell survival rates of human normal cells (GM05757) after the 72- hr treatment of cisplatin with various concentrations. The viability of cells in 96-well plates was measured by MTT assay. This result confirms that cisplatin itself is highly toxic without ionizing radiation.
- Figure 6 illustrates cell survival rates of human normal cells (GM05757) after the 72- hr treatment of Compound A with various concentrations.
- the viability of cells in 96-well plates was measured by MTT assay. This result shows that Compound A itself shows little toxicity up to 200 ⁇ without ionizing radiation.
- Figure 7 illustrates cell survival rates of human normal cells (GM05757) after the 72- hr treatment of Compound B with various concentrations.
- the viability of cells in 96-well plates was measured by MTT assay. This result shows that Compound B itself shows little toxicity up to 200 ⁇ without ionizing radiation.
- Figure 8 illustrates cell survival rates of human normal cells (GM05757) after the 72- hr treatment of Compound C with various concentrations. The viability of cells in 96-well plates was measured by MTT assay. This result shows that Compound C itself shows little toxicity up to 200 ⁇ without ionizing radiation.
- Figure 9 illustrates cell survival rates of human normal cells (GM05757) after the 72- hr treatment of Compound D with various concentrations.
- the viability of cells in 96-well plates was measured by MTT assay. This result shows that Compound D itself shows little toxicity up to 200 ⁇ without ionizing radiation.
- Figure 10 illustrates cell survival rates of human normal cells (GM05757) after the 12-hr treatment of cisplatin with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. At 12 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. This result confirms that in spite of being highly toxic as a chemotherapeutic drug, cisplatin induced essentially no radiation toxicity. Therefore cisplatin has been used as a radiosensitizer in the clinic.
- Figure 11 illustrates cell survival rates of human normal cells (GM05757) after the 12-hr treatment of Compound A with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 12 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. This result shows that the cell viability was independent of radiation doses, indicating that compound A induced no radiation toxicity.
- Figure 12 illustrates cell survival rates of human normal cells (GM05757) after the 12-hr treatment of Compound B with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 12 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. This result shows that the cell viability was independent of radiation doses, indicating that compound B induced no radiation toxicity.
- Figure 13 illustrates cell survival rates of human normal cells (GM05757) after the 12-hr treatment of Compound D with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 12 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. This result shows that the cell viability was independent of radiation doses, indicating that compound D induced no radiation toxicity.
- Figure 14 illustrates cell survival rates of human cervical cancer (HeLa) cells after the 12-hr treatment of Compound A with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cancer cells to X-ray by Compound A was observed.
- HeLa human cervical cancer
- Figure 15 illustrates cell survival rates of cisplatin-resistant human ovarian cancer (HTB-161) cells after the 12-hr treatment of Compound A with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cisplatin-resistant cancer cells to X-ray by Compound A was observed.
- HTB-161 cisplatin-resistant human ovarian cancer
- Figure 16 illustrates cell survival rates of human cervical cancer (ME- 180) cells after the 12-hr treatment of Compound B with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cancer cells to X-ray by Compound B was observed.
- Figure 17 illustrates cell survival rates of cisplatin-resistant human lung cancer (HTB- 161) cells after the 12-hr treatment of Compound B with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation.
- the survival curves of the treated cells was measured by 18-day clonogenic assay. A significant enhancement in the radiosensitivity of cisplatin- resistant cancer cells to X-ray by Compound B was observed.
- Figure 18 illustrates cell survival rates of human cervical cancer (HeLa) cells after the 12-hr treatment of Compound C with various concentrations, followed by 0 and 20 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cancer cells to X-ray by Compound C was observed.
- HeLa human cervical cancer
- Figure 19 illustrates cell survival rates of human cervical cancer (HeLa) cells after the 12-hr treatment of Compound D with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cancer cells to X-ray by Compound D was observed.
- HeLa human cervical cancer
- Figure 20 illustrates cell survival rates of human cervical cancer (ME- 180) cells after the 12-hr treatment of Compound D with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96-well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cancer cells to X-ray by Compound D was observed.
- Figure 21 illustrates cell survival rates of of of cisplatin-resistant human ovarian cancer (HTB-161) cells after the treatment of Compound D with various concentrations, followed by 0-7.5 Gy 225 keV X-ray irradiation. 6 days after irradiation, the viability of the cells in 96- well plates was measured by MTT assay. A significant enhancement in the radiosensitivity of cisplatin-resistant cancer cells to X-ray by Compound D was observed.
- Figure 22 shows the survival rate of mice IP injected with Compound B at various concentrations (0, 5 and 7 mg/kg) given daily for 10 days. The results show that Compound B has no overall toxicity in mice.
- Figure 23 shows mouse weight variation for the treatments of Compound B at various concentrations (0, 5 and 7 mg/kg) given daily for 10 days by IP injection. The results show that Compound B has no overall toxicity in mice.
- Figure 24 shows mouse serum proile variation for the treatments of Compound B at various concentrations (0, 5 and 7 mg/kg) given daily for 10 days. The results show no acute toxicity induced by Compound B.
- Figure 25 shows mouse electrolyte variation for the treatments of Compound B at various concentrations (0, 5 and 7 mg/kg) given daily for 10 days. The results show no acute toxicity induced by Compound B.
- Figure 26 shows mouse liver protein profile variation for the treatments of Compound B at various concentrations (0, 5 and 7 mg/kg) given daily for 10 days. The results show no acute toxicity induced by Compound B.
- Figure 27 shows the pharmacokinetics result that compound B was detected in the plasma. The highest concentration of compound B was observed at about 20 minutes after the i.p. injection and dropped to neraly zero at about 3 hr after injection.
- Figure 28 shows tumor volume growth curves for the treatments of control, 7mg/kg Compound B only, 15 Gy 225 keV x-ray only, 7mg/mg Compound B plus 15 Gy 225 keV x- ray.
- Compound B was given by IP injection at lhr prior to x-ray irradiation.
- Figure 29 shows photos of tumor growths in mice at 19 days after treatments of 7 mg/kg Compound B and/or 15 Gy x-rays ionizing radiation (IR), compared to the control.
- Figure 30 shows tumor volumes and MRI images of mice at Day 21 after treatments of 7 mg/kg Compound B and/or 15 Gy x-rays ionizing radiation (IR), compared to the control.
- the combination of Compound B with IR resulted in a most significant shrinkage of the tumor in mice.
- the present disclosure relates to radiosensitizer compounds useful in combination with ionizing radiation, e.g. to enhance radiation therapy.
- the compounds have been demonstrated to enhance the effects of radiation therapy in a synergistic manner.
- the present disclosure also relates to a combination therapy for treating cancer and other disorders treatable by radiation therapy.
- compounds, compositions, methods, uses, commercial packages and kits relating to the radiosensitizing compounds While the compounds disclosed herein are effective radiosensitisers, they were found to be significantly less toxic to normal cells than the platinum-containing
- radiosensitizer cisplatin, even at doses up to 200 ⁇ .
- a "radiosenzitizer compound” refers to a non-platinum-containing compound as defined herein that may be used to enhance radiotherapy, for example, in the treatment of cancer and other disorders treatable by ionizing radiation.
- the terms “compound”, “molecule” and “agent” may be used interchangeably herein.
- the radiosensitizer compounds of the present disclosure interact with ionization radiation to enhance the effect of said ionizing radiation thereby providing a synergistic combination.
- the radiosensitizer compounds are believed to be highly reactive with prehydrated electrons (e pre ⁇ ) generated by radiolysis of water in the cells exposed to ionizing radiation.
- Some general features of the radiosensitizing compounds of the present disclosure are that they comprise an aromatic ring (rather than a platinum coordinating ion), coupled to one or more electron transfer promoters, such as NH 2 groups, and one or more electron-accepting leaving groups, such as halogen.
- the radiosensitizer compounds disclosed herein are nontoxic toward normal cells, even at very high doses up to 200 ⁇ , while their combination with ionizing radiation can effectively kill the cancer cells in vitro or in vivo.
- the compounds are believed to have a low affinity to normal cells, possibly due to the lack of a reductive intracellular environment, and to have no or low systematic and acute toxicity in the body. They are highly effective radiosensitizing agents that can enhance the preferential killing of cancer cells by ionizing radiation and are therefore believed to be useful for enhancing radiotherapy of cancer and potentially other disorders treatable by radiation.
- the disclosed compounds are expected to be superior to cisplatin, which is highly toxic, and halopyrimidines, which are relatively ineffective as radiosensitizers.
- the biocompatible radiosensitizer compound for use in combination with ionizing radiation has the general formula I:
- A is a 5- or 6-membered aryl or heteroaryl ring containing 0-2 ring heteroatoms selected from the group consisting of N, O and S, the remaining ring atoms being carbon
- R a and R b are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl or an electron transfer promoter, wherein at least one of R a and R b is an electron transfer promoter;
- R c is, independently for each occurrence, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl, a leaving group, or two adjacent R c groups taken together with the ring atoms to which they are attached form a
- the radiosensitizer compound has the general formula II:
- X and Y are independently C-R 3 or N;
- R 3 is H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, or heteroaryl;
- R a and R b are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, heteroaryl or an electron transfer promoter, wherein at least one of R a and R b is an electron transfer promoter;
- R 1 and R 2 are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl,
- the radiosensitizer compound has the general formula III,
- R 3 is H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, or heteroaryl
- R 1 and R 2 are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, heteroaryl, or a leaving group; wherein at least one of R 1 and R 2 is a leaving group, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl and heteroaryl moieties is optionally
- the core of the molecule is a conjugated or aromatic ring system that may consist of one aryl or heteroaryl ring (monocyclic), or may consist of a multiple rings (polycyclic).
- the aromatic core may comprise 2 or 3 fused rings to form a bi-cyclic, or tri-cyclic core, respectively.
- Aromatic ring systems are capable of transporting an electron transiently stabilized by the electron transfer promoter, such as NH 2 groups, acquired through reaction with a prehydrated electron, to the site of a leaving group. When a temporary anion of the molecule is formed, it can rapidly cause a loss of the leaving group, such as a stable anion, and produce a highly reactive neutral radical.
- the aromatic core may be single 5- or 6-membered aromatic ring, such as aryl or heteroaryl.
- 6-membered mono-cyclic rings include, but are not limited to, benzene, pyridine, and pyrazine.
- 5-membered heteroaryl rings include, but are not limited to, furan, pyrole, thiophene and oxazole.
- the compound comprises a 5- or 6-membered aryl or heteroaryl ring containing 0-2 ring heteroatoms selected from the group consisting of N, O and S, the remaining ring atoms being carbon.
- the core is a 6-membered aromatic ring containing 0, 1 or 2 ring heteroatoms selected from N, such as benzene (0 N), pyridine (1 N), or pyrazine (2 N).
- the core is a 6-membered aryl ring containing 0 ring heteroatoms, such as benzene.
- the core is a 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms selected from N, such as pyridine (1 N) or pyrazine (2 N).
- substituents adjacent one another on the core ring may, together with the ring atoms to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, thereby forming a polycyclic ring system.
- fused bi-cyclic 6-membered rings include, but are not limited to, naphthalene, quinolone, isoquinoline, quinoxaline, quinazoline, cinnoline and phthalazine.
- fused tri-cyclic 6-membered rings include, but are not limited to, anthracene, phenanthracene, and acridine.
- a polycyclic ring system may comprise a combination of 5- and 6-membered ring moieties.
- the core is a polycyclic ring system, it is desirable that the compound as a whole retain its ability to transiently stabilize and transport an electron to the site of a leaving group such that a reactive radical can be formed.
- the radiosensitizer compounds of the present disclosure comprise one or more electron transfer promoters coupled to the aromatic ring system (e.g. one or both of R a and R b in Formula I or II, and -NH 2 in Formula III).
- a "electron transfer promoter”, as used herein, is an atom or functional group that assists in capturing and transiently stabilizing a prehydrated electron. The electron is then transported through the aromatic ring system to cause breakage of a bond between a ring carbon atom and a leaving group. Once the leaving group breaks away from the ring, the resulting neutral radical is highly reactive, e.g. with DNA to cause DNA damage and death of a cancer cell.
- the electron transfer promoter preferably two electron transfer promoters in close proximity to one another, activates the radiosensitizer molecule, making it more reactive with a prehydrated electron generated during radiolysis.
- the electron transfer promoters may be the same or different. In some embodiments, the electron transfer promoters are the same. In preferred embodiments, two electron transfer promoters are positioned in close proximity to one another on the ring, e.g. on adjacent ring carbons. This is a particularly effective arrangement for capturing and transferring electrons, particularly when strong leaving groups are present on the ring.
- electron transfer promoters include but are not limited to -NH 3 ⁇ 4 -NHR, - NR 2 , -OH, -OR, -0-, -NHCOCH3, -NHCOR, -OCH3 -OR, -CH 3 , -C 2 H 5 , R, and -C 6 H 5 .
- the electron transfer promoter is selected from the group consisting of-NH 2 , -NHR, -NR 2 , -OH, -OR, -0-, -NHCOCH 3 , - NHCOR, -OCH 3 -OR, -CH 3 , -C 2 H 5 , R, and -C 6 H 5 .
- the electron transfer promoter is selected from the group consisting of -NH 3 ⁇ 4 -NHR, - R 2 , -OH, - HCOCH3, - HCOR, -OCH3, and -OR. In some embodiments, e.g.
- the electron transfer promoter is a selected form the group consisting of - H 2 , - NHR, -NR 2 , -OH, and -0-. In some embodiments, the electron transfer promoter is selected from the group consisting of -NH 2 , -NHR, -NR 2 , and -OH. In some embodiments, the electron transfer promoter is selected form the group consisting of -NH 2 , -NHR, -NR 2 . In some embodiments, the electron transfer promoter is -NH 2 . In some embodiments, the electron transfer promoter is -NHR. In some embodiments, the electron transfer promoter is -NR 2 . In some embodiments, e.g. of Formula I, II or II, the electron transfer promoter is selected from the group consisting of -NHCOCH3, -NHCOR, -OCH3, and -OR.
- R in any of the above may, for example, be substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl groups.
- each R may be the same or different.
- R is substituted or unsubstituted alkyl.
- R a and R b are an electron transfer promoter. In some embodiments, both of R a and R b is an electron transfer promoter. In some embodiments, both of R a and R b are the same electron transfer promoter. In some embodiments, R a and R b are positioned on adjacent ring atoms. In some embodiments, a leaving group is positioned meta, ortho or para to the electron transfer promoter. In some embodiments, a leaving group is positioned meta to the electron transfer promoter. In some embodiments, a leaving group is positioned ortho to the electron transfer promoter. In some embodiments, a leaving group is positioned para to the electron transfer promoter.
- the radiosensitizer compounds of the present disclosure comprise one or more leaving groups coupled to the aromatic ring system (e.g. one or both of R 1 and R 2 in Formula I, II or III). Additional leaving groups may also be provided as substituents on the aromatic ring. Where there are multiple leaving groups, the leaving groups may be the same or different. In some embodiments, the leaving groups are the same.
- the presence of a strong leaving group on the molecule can enhance the reactivity of the molecule with prehydrated electrons generated during radiolysis, particularly when the leaving group is operatively positioned with respect to the electron transfer promoter (e.g. within 1 ,2 or 3 ring atoms).
- a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules, but in either case it is crucial that the leaving group be able to stabilize the additional electron density that results from bond heterolysis. Common anionic leaving groups include, but are not limited to, halides, such as, CI, Br, and I (e.g. CI " , Br " , ⁇ ), and sulfonate esters, such as tosylate, nosylate, mesylate and triflate. Other leaving groups include, but are not limited to, dinitrogen, dialkyl ethers, alcohols, nitrates, phosphates, and other inorganic esters. In accordance with the present disclosure, the leaving group must be a biocompatible leaving group.
- the leaving group is an anionic leaving group.
- the leaving group is halogen.
- the leaving group is CI, Br or I.
- the leaving group is CI.
- the leaving group is Br.
- the leaving group is I.
- two R c groups on Ring A are leaving groups.
- the leaving groups are halogen selected from the group consisting of CI, Br and I.
- Ring A is a 6-membered aryl or heteroaryl ring, such as benzene, pyridine or pyrazine, each of R a and R b are H 2 ; two R c substituents on Ring A are halogen each positioned meta to one of R a and R b on Ring A; and any remaining R c groups are as defined herein.
- Ring A is benzene. In some embodiments, where Ring A is benzene, the remaining carbons on Ring A are unsubstituted carbon. In some embodiments, Ring A is pyridine. In some embodiments, where Ring A is pyridine, the remaining carbon on Ring A is unsubstituted. In some embodiments, Ring A is pyrazine.
- the leaving group is positioned ortho (e.g. within 1 ring atom), meta (e.g. within 2 ring atoms) or para (e.g. within 3 ring atoms) to the electron transfer promoter.
- carbon atoms may be unsubstituted or substituted, unless otherwise specified.
- ring carbon atoms may be unsubstituted or substituted.
- Substituents may include, for example, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaiyl groups.
- Each of the carbon-based substituents e.g.
- alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaiyl) may optionally be further sub stituted .
- R c is, independently for each occurrence, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaiyl, a leaving group, or two adjacent R c groups taken together with the ring atoms to which they are attached form a 5- or 6- membered saturated, partially saturated or unsaturated ring which contains 0-2 ring heteroatoms selected from N, O and S and which can be optionally substituted with 1-4 R d ; wherein at least one R c is a leaving group.
- n 1-4 (e.g. 1, 2, 3 or 4).
- Each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaiyl moieties may be optionally substituted.
- R a and R b are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaiyl or an electron transfer promoter, wherein at least one of Ra and Rb is an electron transfer promoter.
- Each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaiyl moieties may be optionally substituted.
- R 3 may H, OH, halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, or heteroaiyl.
- alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl and heteroaiyl moieties may be optionally substituted.
- R 1 and R 2 are, independently, H, OH, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl, heteroaiyl, or a leaving group.
- Each of the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aiyl, heterocyclyl and heteroaiyl moieties may be optionally substituted.
- at least one of ⁇ and R 2 is a leaving group.
- both R 1 and R 2 are leaving groups, where R 1 and R 2 may be the same or different.
- optionally substituted carbon-based groups above may further include one or more functional groups on the substituent, such as hydroxyl, amino, amido, cyano, nitro, carboxyl, ester, ether, ketone, aldehyde, aiyl, and heteroaiyl, or a combination thereof.
- radiosensitizing compounds of the present disclosure are shown below:
- the radiosensitizer compound has a comprises a 6-membered aryl or heteroaryl ring selected from benzene, pyridine and pyrazine; two H 2 electron transfer promoter groups positioned adjacent to one another on the ring, and at least one halogen leaving group positioned meta to one of the H 2 groups.
- a halogen leaving group is positioned meta to each of the H 2 groups. It has been found that compounds having this structure are highly effective.
- the radiosensitizer compound is selected from the group consisting of:
- the radiosensitizer compound is selected from the group consisting of:
- the radiosensitizer compound is selected from the group consisting of:
- the electron affinity (E A ) of an atom or molecule is generally defined as the energy change when an electron is added to a neutral atom or molecule to form a negative ion:
- a positive electron affinity is a desirable property as it relates to the reactivity of the radiosensitizer molecules with prehydrated electrons (e pre ) generated during radiolysis. It is therefore preferable that the radiosensitizer molecules have an electron affinity greater than 0.0 eV.
- the electron affinity of the radiosensitizer compounds (RSCs) disclosed herein is positive (e.g. > 0.0 eV).
- the electron affinity the RSC is between about 0.0 eV and about +5.0 eV, between about 0.0 eV and about +4.0 eV, between about 0.0 eV and about +3.0 eV, or between about 0.0 eV and about +2.5 eV.
- the electron affinity the RSC is between about +0.2 eV and about +5.0 eV, or between about +0.2 eV and about +4.0 eV, or between about +0.2 eV and about +3.0, or between about +0.2 eV and about +2.0 eV.
- the electron affinity the RSC is between about +0.5 eV and about +3.0 eV, between about +0.5 eV and about +2.5 eV, between about +0.5 eV and about +2.0 eV, or between about +0.5 eV and about +1.5 eV.
- the electron affinity of a molecule may be determined by skilled persons using methods known in the art.
- the radiosensitizer compounds of the present disclosure may be radiolabelled, i.e., said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number: ordinarily found in nature.
- exemplary radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3H, 14C, 32P, 35S, 43F and 36CI, respectively.
- Radiolabelled compounds can generally be prepared by methods well known to those skilled in the art. In some cases, such radiolabelled compounds can be prepared by carrying out general synthetic procedures and substituting a readily available radiolabelled reagent for a non-radiolabelled reagent.
- aryl means a substituted or unsubstituted aromatic hydrocarbon ring system having 6-14 ring atoms, e.g. 6 ring atoms, which may be a mono-, bi- or tri-cyclic aromatic ring system, including but not limited to those aryl groups in the molecules disclosed or exemplified herein.
- aryl denotes a 6-membered aromatic ring, which may optionally be fused to one or more aromatic or non-aromatic rings.
- alkyl denotes a saturated linear or branched hydrocarbon group containing, e.g., from 1 to 10 carbon atoms, e.g.
- alkyl typically refers to a linear or branched hydrocarbon group containing 1-6 carbon atoms (e.g. Ci-C 6 alkyl).
- Ci-C 6 alkyl is intended to include Ci, C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups.
- alkyl groups may be substituted or unsubstituted.
- alkoxy denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom, e.g. methoxy and ethoxy. Alkoxy can optionally be substituted with one or more substituents.
- alkoxy refers to groups -O-alkyl, wherein the alkyl group is as defined above. Examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the like.
- alkoxy groups may be substituted or unsubstituted.
- alkenyl denotes a carbon chain of from 2 to 12, e.g. from 2 to 6, carbon atoms comprising a double bond in its chain.
- C 2- 6-alkenyl groups include, e.g., ethenyl, propen-l-yl, propen-2-yl, buten-l-yl, buten-3-yl, penten-l-yl, penten-2-yl, penten-3- yl, penten-4-yl, hexen-l-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl.
- alkenyl groups may be substituted or unsubstituted.
- alkynyl is intended to include hydrocarbon chains of either linear or branched configuration, having one or more carbon-carbon triple bonds that may occur in any stable point along the chain.
- alkynyl groups refer refers to groups having 2 to 8, e.g. 2 to 6 carbons. Examples of “alkynyl” include, but are not limited to prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5- ynyl, etc.
- alkynyl groups may be substituted or unsubstituted.
- cycloalkyl denotes any stable cyclic or polycyclic hydrocarbon group containing 3 to 13 carbons, e.g., e.g. from 3 to 6 carbons. As in the case of other alkyl moieties, cycloalkyl can optionally be substituted with one or more substituents.
- cycloalkenyl includes any stable cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon atoms, e.g. 5 to 8 carbon atoms, which contains one or more unsaturated carbon-carbon double bonds that may occur in any point along the cycle. As in the case of other alkenyl moieties, cycloalkenyl may optionally be substituted.
- Cycloalkynyl includes any stable cyclic or polycyclic hydrocarbon groups of from 5 to
- heterocyclyl refers to non-aromatic ring systems having five to fourteen ring atoms, e.g. 5 to 10 ring atoms, in which one or more ring carbons, e.g. 1 to 4, are each replaced by a heteroatom such as N, O, or S, the rest of the ring members being carbon atoms.
- the heterocyclyl can optionally be substituted with one or more substituents, independently at each position.
- heteroaryl refers to a mono-or polycyclic aromatic ring system having 5 - 14 ring atoms, e.g. 5 or 6 ring atoms, containing at least one ring heteroatom selected from N, O, or S, the rest of the ring members being carbon atoms. Heteroaryl moieties can optionally be substituted, independently at each position. Examples of heteroaryl moieties include but are not limited to those in the molecules disclosed or exemplified herein.
- aliphatic group refers to, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl or non-aromatic heterocyclic groups. Aliphatic groups may contain one or more substituents.
- amine may refer to an organic compound or functional group (i.e. amino) that contains a basic nitrogen atom with a lone electron pair, including, primary amine ( RH 2 ), secondary amine ( RiR 2 H), and tertiary amine ( RiR 2 R 3 ) where each R may be the same or different. Also, two R groups may denote members of a ring, e.g., where N is a heteroatom in a heterocyclic or heteroaryl ring.
- compositions disclosed herein are pharmaceutically acceptable salts the compounds disclosed herein.
- the descriptions of compounds of the present application are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
- the radiosensitizer compounds disclosed herein may be present in a pharmaceutical composition, or in one of various pharmaceutical dosage forms, suitable for administration to a subject.
- Pharmaceutical compositions and dosage forms comprising the radiosensitizer compounds of the present disclosure are useful for enhancing the effects of ionizing radiation.
- a “pharmaceutical composition” refers to a combination of ingredients that facilitates administration of one or more agents of interest (e.g. a radiosensitizer compound) to a subject.
- a pharmaceutical composition generally comprises one or more agents of interest in admixture with one or more pharmaceutically acceptable carriers or diluents.
- Many pharmaceutically-acceptable “carriers” and “diluents” are known in the art and these generally refer to a pharmaceutically-acceptable materials, compositions, or vehicles, including liquid or solid fillers, diluents, excipients, solvents, binders, or encapsulating materials.
- each component in the composition must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation.
- Each component the composition, including the radiosenzitizer compound must also be “biocompatible", such that the composition is suitable for contact with the tissues or organs of a subject without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- compositions disclosed herein may be formulated in any suitable dosage form, including single-unit and multiple-unit dosage forms.
- Exemplary dosage forms include, for example, a liquid, a solution, a suspension, an emulsion, a concentrate, a powder, a paste, a gel, a gum, a drop, a tablet, a capsule or a microcapsule.
- the dosage form is a liquid.
- the liquid is a solution, a suspension, or an emulsion.
- the radiosensitizer compounds and pharmaceutical compositions containing them may be administered by any suitable route of administration.
- the radiosensitizer compound be administered locally (e.g. into a tumor), regionally (e.g. into a body cavity) or systemically (e.g. into a blood vessel, such as a vein or artery).
- the radiosensitizer compound is formulated for enteral administration, topical administration, parenteral administration, or nasal administration.
- Enteral administration may comprise, for example, oral administration.
- the radiosensitizer compound or composition is formulated for parenteral administration.
- Parenteral administration may comprise, for example, intravenous, intraarterial, intracerebral, intraperitoneal, intramuscular, subcutaneous, intracardiac, or intraosseous administration.
- the parenteral administration is intravenous administration, e.g. injection or infusion.
- the parenteral administration is intraarterial administration.
- the parenteral administration is intraperitoneal administration.
- the parenteral administration is systemic or regional. In some embodiments, the parenteral administration is systemic. In some embodiments, the radiosensitizer compound or composition is administered intravenously. DOSAGE OF RADIO SENZITIZER
- the radiosensitizer compound or composition may be administered according to any treatment regimen deemed appropriate by the skilled worker (e.g. clinician).
- the dosage requirements of the radiosensitizer compounds and pharmaceutical compositions containing them will vary with the particular combinations employed, the route of administration and the particular cancer and cancer patient being treated. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter, the dosage is increased until the optimum effect under the circumstances is reached.
- the radiosensitizer compounds and compositions according to the present invention are administered at a concentration that will afford effective results without causing any harmful or deleterious side effects. As with any chemo-radiotherapy, a certain degree of toxic side effects may be considered acceptable.
- a sufficient amount of the radiosensitizing compound should be employed to effectively react with the particular dose of ionizing radiation employed.
- a dose of the radiosensitizing compound will be selected such that the radiosensitizing compound does not contribute significant unwanted effects to the combination.
- the effective dosage of the radiosensitizing compound may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, the dosage of ionizing radiation employed, as well as the various physical factors related to the individual being treated.
- the compound is administered in a daily dosage of between about 0.01 mg/kg and about 500 mg/kg, between about 0.1 mg/kg and about 125 mg/kg, between 1 mg/kg and about 50 mg/kg between 1 mg/kg and about 25 mg/kg, between about 0.3 mg/kg and about 15 mg/kg, or between about 0.5 mg/kg and 5 mg/kg, or between about 5 mg/kg and 10 mg/kg .
- the radiosensitizer compounds are substantially non-toxic to normal cells and therefore may be tolerated at relatively high doses (e.g. 10 mg/kg - about 50 mg/kg, or between about 10 mg/kg to about 30 mg/kg).
- the projected daily dosages are expected to vary with route of administration. Thus, parenteral dosing will often be at levels of roughly 10% to 20% of oral dosing levels.
- Radiotherapy is the medical use of ionizing radiation, generally as part of cancer treatment to control or kill malignant cells.
- Ionizing radiation is radiation composed of particles that individually carry enough kinetic energy to liberate an electron from an atom or molecule thereby ionizing it.
- Ionizing radiation sources may include external radiation sources, for example, x-radiation (x-rays), gamma-radiation ( ⁇ -rays), beta-radiation ( ⁇ -rays), neutral or charged particle beams, Auger electron sources, internal radiation sources (brachytherapy or sealed source radiation therapy), and radioisotope sources (systemic radioisotope therapy or unsealed source radiotherapy).
- the radiosensitizer compounds disclosed herein may be used in combination with any suitable source of ionizing radiation that provides electrons capable of reacting with the compounds.
- Ionizing radiation may include X-radiation, gamma-radiation, ⁇ -radiation, neutral or charged particle radiation, internal radiation (sealed source radiation ), Auger electron source, and radioisotope radiation (unsealed source radiotherapy).
- the ionising radiation employed will be X-radiation, ⁇ -radiation or ⁇ -radiation.
- the ionising radiation will be X-radiation.
- the ionising radiation will be ⁇ - radiation.
- the ionising radiation will be ⁇ -radiation.
- DNA damaging factors are also included in the present invention such as UV-irradiation and/or the directed delivery of radiation from a localized internal radiation source (sealed source) or systemic radioisotopes.
- UV-irradiation and/or the directed delivery of radiation from a localized internal radiation source (sealed source) or systemic radioisotopes DOSAGE OF IONIZING RADIATION
- the dosages of ionising radiation will be those known for use in clinical radiotherapy.
- X-rays may be fractionally dosed in daily doses of 1.8-2.0 Gy, 5 days a week for 5-6 weeks. Normally, a total fractionated dose will lie in the range 45-60 Gy.
- Single larger doses, for example 5- 10 Gy may be administered as part of a course of radiotherapy.
- Single doses may be administered intraoperatively.
- Hyperfractionated radiotherapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0.1 Gy per hour over a number of days. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and on the uptake by cells.
- prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
- the optimum dosage may be determined by the practitioner who is treating any particular patient. For example, it may be necessary or desirable to use fractional radiation doses (e.g., 2 Gy/treatment) combined any of the herein mentioned compound doses (e.g., 7 mg/kg/treatment) for multiple treatments (e.g., daily treatments, 5 days a week for 5-6 weeks) in order to achieve the optimal treatment efficacy. In some cases, the doses may be reduced in a combination therapy.
- fractional radiation doses e.g., 2 Gy/treatment
- any of the herein mentioned compound doses e.g., 7 mg/kg/treatment
- multiple treatments e.g., daily treatments, 5 days a week for 5-6 weeks
- the doses may be reduced in a combination therapy.
- contacting cancer cells with a non-platinum-based radiosensitizer compound of the disclosure in combination with ionizing radiation in vitro or in vivo provides an enhanced efficacy of radiotherapy, i.e. synergy, while the compound itself is substantially non-toxic within the usable doses. Furthermore, its combination with ionizing radiation induces no radiation toxicity (i.e, independent of radiation dose).
- the radiosensitizer compounds disclosed herein therefore provide a novel combination therapy for disorders treatable by radiation therapy, such as cancer.
- the combination therapy is thus a chemo- radiotherapy combination that includes a radiosensitizing compound as disclosed herein and ionizing radiation.
- the term "combination therapy” means that, at some point during the treatment, the two components of the combination will interact, in particular, at a target site(s).
- the target site may, for example, be the site of a cancer cell or a tumor.
- the two or more components of the combination therapy are not necessarily administered together at the same time.
- the radiosensitizing compound and the ionizing radiation may, for example, be administered simultaneously (e.g. at substantially the same time), sequentially (e.g. staggered times), or at overlapping intervals.
- the radiosensitizer compound and the ionizing radiation are administered simultaneously (e.g. together at the same time, or within about 30 seconds of each other). In some embodiments, radiosensitizer compound and the ionizing radiation are administered in sequence. In some embodiments, the radiosensitizer compound and the ionizing radiation are administered sequentially, e.g. within 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 5 hours, or more, of each other.
- the radiosensitizer compound is administered before the ionizing radiation, for example, to give the compound sufficient time to reach the target site before applying the radiation. In some embodiments, the radiosensitizer compound is administered about 10 minutes to about 2 hours before the ionizing radiation. In some embodiments, the radiosensitizer compound is administered after the ionizing radiation. In some embodiments, the radiosensitizer compound is administered about 1 minute to about 5 hours after the ionizing radiation.
- timing which will depend on such factors as absorption rate, bioavailability, and half-life.
- the combination therapies disclosed herein are typically administered to individuals who have been diagnosed with cancer. However, in some cases, the combination therapy may be administered to individuals who do not yet show clinical signs of cancer, but who are at risk of developing cancer. Toward this end, the present application also discloses methods for preventing or reducing the risk of developing cancer.
- the combination therapies disclosed herein may also be used to treat a relapse or to prolong a remission.
- the combination therapies disclosed herein may also be used to treat other disorders treatable by radiation therapy, including non-malignant conditions, such as trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification.
- non-malignant conditions such as trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification.
- the present disclosure relates to methods of enhancing radiation therapy.
- the method of enhancing radiotherapy in a subject in need thereof comprises administering an effective amount of a radiosensitizer compound as defined herein to the subject in combination with an effective amount of ionizing radiation.
- the present disclosure provides a method of providing an anti-cancer effect in a cancer cell, comprising: a) administering to the cancer cell an effective amount of a compound as defined herein; and b) administering to the cancer cell an effective amount of ionizing radiation, wherein a) and b) are administered sequentially or simultaneously to thereby provide the anti-cancer effect.
- the anti-cancer effect is killing of the cancer cell.
- the cancer cell is a tumor cell.
- the present disclosure provides a method of treating cancer in a subject in need thereof comprising: a) administering to the subject an effective amount of a compound as defined herein; and b) administering to the subject an effective amount of ionizing radiation, wherein a) and b) are administered sequentially or simultaneously.
- the compound is administered before, during or after administration of the ionizing radiation. In some embodiments, the compound is administered before or during administration of the ionizing radiation. In some embodiments, the compound is administered before administration of the ionizing radiation.
- the present disclosure provides a method of treating cancer in a subject in need thereof comprising, administering to the subject a therapeutically effective amount of a radiosensitizer compound as defined herein before or simultaneously with an effective amount of ionizing radiation.
- the combinations of the present disclosure have a net anticancer effect that is greater than the anticancer effect of the individual components of the combination when administered alone.
- the present disclosure provides a synergistic combination of a radiosensitizer compound as disclosed herein and ionizing radiation.
- the anticancer effect is increased without a concomitant increase in toxic side effects.
- a synergistic combination of a radiosensitizer compound as defined herein and ionizing radiation for the treatment of cancer comprising a radiosensitizer compound as defined herein for use in the manufacture of a medicament for in use in combination with ionizing radiation for the treatment of cancer.
- the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound highly reactive with a prehydrated electron.
- the agent is capable of showing an anticancer effect under ionizing radiation and no systemic and radiation-induced toxic effects.
- the combination is administered in a therapeutically effective amount.
- a method of overcoming cisplatin resistance wherein any of the methods described above are applied to a cell or a cancer that is resistant to cisplatin treatment, or are applied to a subject having a cell or a cancer that is resistant to cisplatin treatment.
- subject refers to a human or an animal to be treated, in particular, a mammal.
- Mammalian animals may include, for example, primate, cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
- the subject is a human, although the compounds disclosed herein are useful in vertinary applications as well.
- subject and patient may be used interchangeably.
- cancer e.g. neoplastic disorder
- cancer cells e.g. neoplastic disorder
- proliferation or division e.g. neoplasia
- a "tumour” e.g. neoplasm
- the methods and combinations disclosed herein may be used in the treatment of cancer, cancer cells, tumors and/or symptoms associated therewith.
- Exemplary types of cancer that may be treated in accordance with the methods, uses and combinations of the present disclosure include, but are not limited to, testicular cancer, bladder cancer, cervical cancer, ovarian cancer, breast cancer, prostate cancer, head cancer, neck cancer, lung cancer (e.g. non small cell lung cancer), endometrial cancer, pancreatic cancer, Kaposi's sarcoma, adrenal cancer, leukemia, stomach cancer, colon cancer, rectal cancer, liver cancer, esophageal cancer, renal cancer, thyroid cancer, uterine cancer, skin cancer, oral cancer, brain cancer, spinal cord cancer, liver cancer, gallbladder cancer.
- testicular cancer bladder cancer, cervical cancer, ovarian cancer, breast cancer, prostate cancer, head cancer, neck cancer, lung cancer (e.g. non small cell lung cancer), endometrial cancer, pancreatic cancer, Kaposi's sarcoma, adrenal cancer, leukemia, stomach cancer, colon cancer, rectal cancer, liver cancer, esophageal cancer, renal cancer, thyroid cancer, uterine
- the cancer may, for example, include sarcoma, carcinoma, melanoma, lymphoma, myeloma, or germ cell tumours.
- the cancer is testicular cancer, bladder cancer, cervical cancer, ovarian cancer, breast cancer, prostate cancer, head cancer, neck cancer, or lung cancer (e.g. non small cell lung cancer).
- an “anti-cancer agent” refers to a therapeutic agent that directly or indirectly kills cancer cells, for example, by triggering apoptosis, or directly or indirectly prevents, stops or reduces the proliferation of cancer cells.
- an “anti-antineoplastic agent” may include more than one therapeutic agent.
- treat include the eradication, removal, amelioration, modification, reduction, management or control of a tumor, tumor cells or cancer, the minimization, prevention or delay of metastasis, or the prolongation of survival of the subject.
- Metastasis refers to the dissemination of tumor cells via lymphatics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.
- an effective amount or “therapeutically effective amount” is intended to mean that amount of a therapeutic component, or components in a combination therapy, that will elicit a desired biological or medical response in a cell, tissue, tumor, system, or subject, which result is generally sought by a researcher, veterinarian, doctor or other clinician or technician.
- the effective amount of a radiosensitizing compound to be administered in combination with ionizing radiation may be an amount sufficient to provide a desired anti-cancer effect in the presence of the ionizing radiation.
- the effective amount of ionizing radiation to be administered in combination with a radiosensitizing compound may be an amount of ionizing radiation sufficient to provide a desired anti-cancer effect in the presence of the compound.
- the effective amount of one or both components may be lower when the components are combined.
- Synergistic combinations are particularly desirable.
- the combination exhibits a synergistic anti-cancer effect.
- the terms “synergistic” and “synergy” imply that the effect of the combined components of the combination is greater than the sum of the effects of the individual components when administered alone.
- an “anticancer effect” may include, but is not limited to, reduction, prevention or elimination of cancer cells, a tumor, or cancer; reduced or inhibited cancer cell proliferation; increased or enhanced killing or apoptosis of cancer cells; reduction or prevention of metastasis, and/or prolonged survival of a subject.
- a desired biological or medical response may be amelioration, alleviation, lessening, or removing of one or more symptoms of cancer, or reduction in one or more toxic side effects associated with a particular cancer treatment.
- inhibiting or “reducing”, e.g. cancer cell proliferation, it is generally meant to slow down, to decrease, or, for example, to stop the amount of cell proliferation, as measured using methods known to those of ordinary skill in the art, by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, when compared to proliferating cells that are either not treated or are not subjected to the methods and combinations of the present application.
- reducing a tumor it is generally meant to reduce the size of a tumour, as measured using methods known to those of ordinary skill in the art, by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, when compared to tumor size before treatment or compared to tumors that are not subjected to the methods and combinations of the present application.
- “increased” or “enhanced” killing or apoptosis of cancer cells it is generally meant an increase in the number of dead or apoptotic cells, as measured using methods known to those of ordinary skill in the art, by, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100%, 200%, 300% or more, when compared to cells that are either not treated or are not subjected to the methods and combinations of the present application.
- An increase in cell killing or apoptosis could also be measured as a decrease in cell viability, as measured using a standard cell viability assay.
- apoptosis refers to an intrinsic cell self-destruction or suicide program.
- cells undergo a cascade of events including cell shrinkage, blebbing of cell membranes and chromatic condensation and fragmentation. These events culminate in cell conversion to clusters of membrane-bound particles (apoptotic bodies), which are thereafter engulfed by macrophages.
- the combination therapy disclosed herein may be administered as a sole therapy or may be used in conjunction with one or more additional therapies, such as surgery or drug therapy.
- the additional therapy may be a cancer therapy including surgery, e.g. to remove a primary tumor, or a therapeutic agent, e.g., an antibiotic, antiinflammatory agent or anticancer agent.
- Anticancer agents may include, for example, classic chemotherapeutic agents, as well as molecular targeted therapeutic agents, biologic therapy agents, and radiotherapeutic agents.
- Anticancer agents used in further combination with the combination therapy of present disclosure may include agents selected from any of the classes known to those of ordinary skill in the art, including, for example, alkylating agents, anti- metabolites, plant alkaloids and terpenoids (e.g., taxanes), topoisomerase inhibitors, antitumor antibiotics, hormonal therapies, molecular targeted agents, and the like.
- an anticancer agent is an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an anti-tumor antibiotic, a tyrosine kinase inhibitor, or an immunosuppressive macrolide.
- the additional agents selected should not significantly interfere with the combination therapy of the present disclosure so as to significantly reduce effectiveness of the combination therapy or enhance unwanted toxic side effects.
- radiosensitizing compounds disclosed herein are useful in combination with ionizing radiation, e.g. for enhancing radiotherapy.
- radiosensitizer compounds as defined herein for enhancing the effects of radiation therapy in a subject receiving said radiation therapy.
- radiosensitizer compounds as defined herein for for use in the treatment of cancer in a subject receiving radiation therapy there are provided radiosensitizer compounds as defined herein for for use in combination with radiation therapy in the treatment of cancer.
- radiosensitizer compounds as defined herein for for use in the manufacture of a medicament for the treatment of cancer in a subject receiving radiation therapy are provided.
- radiosensitizer compounds as defined herein for use in the manufacture of a medicament for use in combination with radiation therapy the treatment of cancer are provided.
- a use of a radiosensitizer compound as defined herein to enhance radiation therapy in a subject receiving said radiation therapy in another aspect, there is provided a use of a radiosensitizer compound as defined herein in the treatment of cancer in a subject receiving radiation therapy. In another aspect, there is provided a use of a radiosensitizer compound as defined herein in the manufacture of a medicament for the treatment of cancer in a subject receiving radiation therapy.
- the subject has a cancer that is resistant to cisplatin treatment.
- the combination is for administration in a therapeutically effective amount.
- the features of the use are as described in any of the embodiments disclosed herein above.
- kits and commercial packages related to the radiosensitizer compounds as disclosed herein for use in combination with ionizing radiation.
- kits or commercial package comprising a radiosensitizer compound as disclosed herein, together with instructions for use in combination with ionizing radiation.
- the instructions are for use in combination with ionizing radiation in the treatment of cancer.
- cisplatin is a well-known DNA- attacking agent, its precise molecular mechanism of action had remained elusive until recently solved [Lu 2007].
- fs- TRLS femtosecond time-resolved laser spectroscopy
- radiosensitizing compounds of the present disclosure comprise an aromatic ring (rather than a platinum coordinating ion), coupled to one or more electron transfer promoters, such as H 2 groups, and one or more leaving groups, such as halogen. Such compounds are demonstrated herein to be effective radiosensitizing compounds.
- such compounds are also demonstrated herein to be significantly less toxic to normal cells than cisplatin.
- the examples provided herein demonstrate that the exemplary compounds are substantially non-toxic to normal cells, even at high doses.
- contacting cancer cells with a non-platinum-based radiosensitizer compound of the disclosure in combination with ionizing radiation in vitro or in vivo provides an enhanced efficacy of radiotherapy, i.e. synergy, while the compound itself is substantially non-toxic within the usable doses. Furthermore, its combination with ionizing radiation induces no radiation toxicity (i.e, independent of radiation dose).
- the non-platinum-based radiosensitizer compound (RSC) is believed to react with a prehydrated electron (e pre ⁇ ) via a DET reaction as follows: e P re ⁇ + RSC ⁇ radical ⁇ DNA damage/cell death.
- the resultant radical can effectively lead to DNA damage and cell death, e.g. DNA damage and cell death in a cancer cell or tumor.
- GM05757 human normal cells
- GM05757 cell line has been widely used as human normal cells in cancer research, particularly in testing new radiosensitizing agents [Choudhury et al. 2009].
- Figure 5 shows that the normal cells were effectively killed by cisplatin in a dose-dependent manner with a measured IC50 of about 10 ⁇ (at which the cell survival rate is 50% with respect to untreated cells), confirming that cisplatin is indeed highly toxic.
- the overall drug toxicity was studied in 6-8 week SCID mice through a survival assay and body weight measurements, and the acute drug toxicity was measured through the following parameters: blood collection and histology, as outlined in Example 6.
- the hepatotoxicity (ALT, ALP, AST), nephrotoxicity (blood BUN, creatinine), and electrolytes (Na, K, etc) were analyzed by UPLC-mass spectroscopy.
- PK pharmacokinetics
- PD pharmacodynamics
- Example 7 Blood samples were collected from the saphenous vein of mice at various time points after IP injection of the compound into the mice at 0-7 mg/kg and then analyzed using HPLC-Mass Spectrometry. First, significant levels of compound B in the blood were detected. Second, Figure 27 shows that the highest concentration of compound B was observed at about 20 minutes after i.p. injection and dropped to nearly zero at about 3 hr.
- the in vivo radiosensitizing (e.g. anticancer) effects of a combination of Compound B and X-ray irradiation were investigated in the xenograft mouse tumor model of human cervical cancer (ME-180), as outlined in Example 8.
- the combination of Compound B with x-ray irradiation significantly enhanced the suppression of tumor growth, compared with the treatments of radiation or Compound only in the tumor model, as can be seen from the tumor (volume) growth curves shown in Figure 28, photos of tumor growths in Figure 29 and tumor volumes and MRI images shown in Figure 30. All of these results show that the combination of Compound B with ionizing radiation resulted in a significant shrinkage of the tumor in mice.
- the disclosed DET reaction mechanism is designed to be preferentially active at tumor cells. In contrast to normal cells, where a RSC will have a low affinity, thus the DET will not occur or its reaction efficiency will be significantly lowered in normal tissue.
- the disclosed compounds will make a naturally targeted radiotherapy of multiple types of cancers, including (but not limited to) as cervical, ovarian, breast, lung, prostate, brain and spinal cord, head and neck, and colorectal cancers.
- Some desired characteristics of the RSCs include one or a combination of the following: (1) biocompatible; (2) effective reaction with weakly-bound electrons (e pre ⁇ ); (3) enhance the radiosensitivity of cancer cells so that lower radiation doses can be used; (4) minimal toxicity (ideally, substantially non-toxic) at doses to be administered; (5) reactive in a hypoxic tumor environment; (6) preferentially reactive with cancer cells; (7) capable of entering a cell and preferably nucleus; and/or (8) applicable to multiple types of tumors.
- Example 1 Femtosecond laser spectroscopic observation of the DET reaction of radiosensitizer compounds (RSCs) with e pre ⁇
- the DET reactions of new radiosensitizers with e pre ⁇ were studied by fs-TRLS [Lu, 2007; 2010].
- our fs laser amplifier system Spectra-Physics, Spitfire
- a intense pump pulse at 322 nm was used to simulate ionizing radiation by 2-photon excitation of a H 2 0 molecule into a higher energy state H 2 0* that then ionizes to produce an e pre ⁇ ; a probe pulse at 333 nm coming at certain delay was used to monitor the DET reaction with e pre ⁇ by detecting transient anion absorbance.
- the gel was prestained with 0.5 ⁇ g/ml ethidium bromide.
- the image of the gel was taken on a FluorChem imaging station (Alpha Innotech) and exhibits various DNA topological forms, including closed-circular supercoiled (SC, undamaged DNA), open circular (C, SSB) and linear form (L, DSB). They were quantified with an AlphaEase FC software.
- the disclosed compounds indeed resulted in DNA double-strand breaks.
- the disclosed compounds have high efficacy in causing DNA damage.
- the disclosed compounds consisting of (mono- or di-)halogen and diamino groups indeed enhanced their efficacy in inducing DNA damage.
- Example 3 In Vitro tests on the toxicity of RSCs in treating human normal cells
- Cisplatin, dichloro-diamino-benzene (Compound A), bromo-diamino-benzene (Compound D), insulin, and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma-Aldrich.
- Dibromo-diamino-benzene (Dibromo-phenylenediamine, Compound B) was obtained from TCI-America.
- Diiodo-diaminobenzene (Compound C) were synthesized, purified and crystalized in our laboratory, and the structures and purity were examined by NMR and mass spectrometry.
- a human skin diploid fibroblast (GM05757 cell line) was obtained from the Coriell Cell Repository directly. Fetal bovine serum (FBS) was obtained from Hyclone Laboratories (UT, USA). The GM05757 normal cells were cultivated with MEM (Hyclone) supplemented with 10% FBS, 100 units/mL penicillin G and 100 ⁇ g/mL streptomycin (Hyclone). The cells were maintained at 37 °C in a humidified atmosphere containing 5% C0 2 .
- FBS Fetal bovine serum
- the radiosensitizing effects of RSCs on cell viability were determined by the 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide (MTT) assay.
- MTT 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide
- the medium was then removed, and the formazan crystals solubilized by 100 L/well DMSO (or alternatively by 100 ⁇ /well SDS and incubated for another 4 h).
- the surviving fraction was determined by measuring the absorbance at 540 nm (570 nm for SDS solubilization) using a Multiskan Spectrum UV/Vis microplate reader (Thermo Scientific), which is directly proportional to the number of viable cells.
- Cisplatin, dichloro-diamino-benzene (Compound A), bromo-diamino-benzene (Compound D), insulin, and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma-Aldrich.
- Dibromo-diamino-benzene (Dibromo-phenylenediamine, Compound B) was obatined from TCI-America.
- Diiodo-diaminobenzene (Compound C) were synthesized, purified and crystalized in our laboratory, and the structures and purity were examined by MR and mass spectrometry.
- a human skin diploid fibroblast (GM05757 cell line) was obtained from the Coriell Cell Repository directly. Fetal bovine serum (FBS) was obtained from Hyclone Laboratories (UT, USA). The GM05757 normal cells were cultivated with MEM (Hyclone) supplemented with 10% FBS, 100 units/mL penicillin G and 100 ⁇ g/mL streptomycin (Hyclone). The cells were maintained at 37 °C in a humidified atmosphere containing 5% C0 2 .
- FBS Fetal bovine serum
- the radiosensitizing effects of RSCs on cell viability were determined by the 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide (MTT) assay.
- MTT 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide
- FIG. 10 shows cell survival rates of human normal cells (GM05757) after the 12-hr treatment of cisplatin with various concentrations, followed by 0-10 Gy 225 keV X-ray irradiation.
- the viability of cells in 96- well plates was measured by MTT at 12 days after irradiation. This result shows that the normal cell viability was independent of radiation dose. This confirms that in spite of being highly toxic as a chemotherapeutic drug, cisplatin induced essentially no radiation toxicity.
- the disclosed RSCs have a low affinity to normal cells and therefore a low toxicity with and without the presence of ionizing radiation.
- Example 5 In Vitro Radiosensitizing Results of RSCs in treating various cancer cells
- Cisplatin, dichloro-diamino-benzene (Compound A), bromo-diamino-benzene (Compound D), insulin, and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma-Aldrich.
- Dibromo-diamino-benzene (Dibromo-phenylenediamine, Compound B) was obatined from TCI— America.
- Diiodo-diaminobenzene (Compound C) were synthesized, purified and crystalized in our laboratory, and the structures and purity were examined by MR and mass spectrometry.
- a human skin diploid fibroblast (GM05757 cell line) was obtained from the Coriell Cell Repository directly, while the human cervical cancer cell line (HeLa, ATCC#: CCL-2; or ME-180), human ovarian cancer cell line (NIH VCAR-3, ATCC#: HTB-161) and human lung cancer cell line (A549, ATCC#: CCL-185TM ), together with RPMI 1640, F-12K, McCoy's 5 A and L-15 culture media, were obtained from the American Type Culture Collection (ATCC) directly.
- the GM05757 normal cells and HeLa cells were cultivated with MEM (Hyclone) supplemented with 10% FBS, 100 units/mL penicillin G and 100 ⁇ g/mL streptomycin (Hyclone).
- the complete growth media for ME-180, NIH VCAR-3, A549 and MDA-MB -231 cells were the ATCC-formulated McCoy's 5 A Medium supplemented with 10% FBS, RPMI 1640 medium with 20%, F-12K medium with 10% FBS, and L-15 Medium (Leibovitz) with 10% FBS, respectively.
- the cells were maintained at 37 °C in a humidified atmosphere containing 5% C0 2 .
- the radiosensitizing effects of RSCs on cell viability were determined by the 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide (MTT) assay.
- MTT 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide
- Compound A/B/C/D enhances the effectiveness of ionizing radiation to kill tumor cells but no normal cells.
- the RSCs are expected to enhance the efficacy of radiotherapy while induce minimal or no toxic side effects in human cancer patients.
- the three groups (five 6-8 week SCID mice/group) in the experiment were: (1) control article (5% EtOH/medium); (2) Compound B 5 mg/kg in 5% EtOH/medium; and (3) Compound B 7 mg/kg in 5% EtOH/medium, as shown in Table 1. Compound B was injected IP every day for 10 days.
- mice Dose Route (nL/20g) (Days)
- IP intraperitoneally
- mice The overall drug toxicity in mice was observed by a survival assay and body weight measurements, and the acute drug toxicity was measured by blood collection and histology.
- mice All animals were observed post administration, and at least once a day, more if deemed necessary, during the pre-treatment and treatment periods for mortality and morbidity. In particular, animals were monitored for signs of ill health such as body weight loss, change in appetite, behavior changes such as altered gait, lethargy and gross manifestations of stress.
- the overall drug toxicity was studied in 6-8 week SCID mice through a survival assay and body weight measurements, and the acute drug toxicity was studied by measurements of the hepatotoxicity (ALT, ALP, AST), nephrotoxicity (blood BUN, creatinine), and electrolytes (Na, K, etc).
- the survival rate of mice was 100%, that is, Compound B exhibited non-toxicity and had no impact on mice survival.
- Figure 23 Compound B showed no effect on the weight of mice with time, exhibiting no physical toxicity.
- Blood samples were collected from the saphenous vein of mice at various time points after IP injection of the compound into the mice and then analyzed using HPLC-Mass Spectrometry.
- PK pharmacokinetics
- PD pharmacodynamics
- Example 8 In vivo test of Compound B in the xenograft mouse model of human cervical cancer (ME-180) in female SCID mice 8.1 Materials and Protocol
- ME- 180 human cervical cancer cells were cultured in the ATCC-formulated
- McCoy's 5A Medium supplemented with 10% FBS.
- the cells in a flask were maintained at 37 °C in a humidified atmosphere containing 5% C0 2 .
- the cells were rinsed with PBS, trypsined for detachment from the bottom of the flask, mixed with fresh growth medium, and centrifuged to remove the supernatant.
- the cells were re-suspend with fresh medium to appropriate concentration for inoculation. Injection volume was 50 ⁇ (1 x 10 6 cells) per animal.
- ME- 180 tumour cells were implanted subcutaneously into female SCID mice (age 6-8 weeks) in a volume of 50 ⁇ _, into the left gastrocneumius muscle using a 27-gauge needle. This was established as a subcutaneous (SC) xenograft mouse model of human cervical cancer.
- mice were individually weighed and injected intraperitoneally according to body weight for an injection concentration as outlined in the study group table above.
- the injection volume was based on 200 ⁇ L ⁇ per 20 g mouse.
- the skin surface was wiped down with 70% isopropyl alcohol to clean the injection site. Radiation was given using X-rad 225 targeted irradiator to the tumors. 8.1.5 Data Collection
- Tumor size was measured as a function of time to assess tumor growth delay associated with treatment using slide caliper and micro MRI. Animals were also weighed at the time of tumour measurement. Tumours in mice were allowed to grow to a maximum of 1000 mm 3 before termination.
- mice All animals were observed post administration, and at least once a day, more if deemed necessary, during the pre-treatment and treatment periods for mortality and morbidity. In particular, animals were monitored for signs of ill health such as body weight loss, change in appetite, behaviour changes such as altered gait, lethargy and gross manifestations of stress.
- the in vivo radiosensitizing (e.g. anticancer) effects of a combination of Compound B and X-ray irradiation were investigated in the xenograft mouse tumor model of human cervical cancer (ME-180). As shown in Figure 28-30, it is clearly seen the combination of Compound B with x-ray irradiation significantly enhanced the suppression of tumor growth, compared with the treatments of radiation or Compound only in the tumor model. The results show that compound B in combination with ionizing radiation resulted in a very significant tumor growth delay in vivo till 21 days.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015548130A JP6321673B2 (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
US14/654,165 US9655965B2 (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
CN201380073147.7A CN105164107B (en) | 2012-12-20 | 2013-12-20 | For with radiating the radiosensitization immunomodulator compounds being used in combination |
AU2013362757A AU2013362757B2 (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
MX2015008010A MX2015008010A (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation. |
CA2895526A CA2895526C (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
EP13865418.1A EP2935215B1 (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
KR1020157019682A KR102278760B1 (en) | 2012-12-20 | 2013-12-20 | Halogen- and diamino-containing radiosensitizer compounds for use in combination with radiation |
BR112015014855A BR112015014855A2 (en) | 2012-12-20 | 2013-12-20 | radiosensitizing compounds for use in combination with radiation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261797983P | 2012-12-20 | 2012-12-20 | |
US61/797,983 | 2012-12-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014094178A1 true WO2014094178A1 (en) | 2014-06-26 |
Family
ID=50977492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2013/051005 WO2014094178A1 (en) | 2012-12-20 | 2013-12-20 | Radiosensitizer compounds for use in combination with radiation |
Country Status (10)
Country | Link |
---|---|
US (1) | US9655965B2 (en) |
EP (1) | EP2935215B1 (en) |
JP (1) | JP6321673B2 (en) |
KR (1) | KR102278760B1 (en) |
CN (1) | CN105164107B (en) |
AU (1) | AU2013362757B2 (en) |
BR (1) | BR112015014855A2 (en) |
CA (1) | CA2895526C (en) |
MX (1) | MX2015008010A (en) |
WO (1) | WO2014094178A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015051458A1 (en) | 2013-10-08 | 2015-04-16 | Lu qing-bin | Non-platimun-based anti-cancer compounds for use in targeted chemotherapy |
WO2021224186A1 (en) * | 2020-05-04 | 2021-11-11 | Institut Curie | New pyridine derivatives as radiosensitizers |
US11311552B2 (en) * | 2015-04-02 | 2022-04-26 | Proximagen, Llc | Therapies for cancer |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106045932B (en) * | 2016-06-06 | 2018-05-15 | 浙江省肿瘤医院 | A kind of compound and its application with radiosensitizing effect |
CN114478524A (en) * | 2022-03-15 | 2022-05-13 | 江苏省肿瘤医院 | 1, 8-naphthyridine compound and application thereof |
CN114560799A (en) * | 2022-03-15 | 2022-05-31 | 江苏省肿瘤医院 | Nitrile group substituted phenyl compound and application thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006067466A2 (en) | 2004-12-22 | 2006-06-29 | The Wellcome Trust Limited | Pyrazines and pyridines and derivatives thereof as therapeutic compounds |
CA2603810A1 (en) | 2005-04-01 | 2006-10-12 | Taiho Pharmaceutical Co., Ltd. | Potentiator for radiation therapy comprising pyridine derivative as active ingredient |
WO2008042282A2 (en) | 2006-09-28 | 2008-04-10 | Exelixis, Inc. | Imidazole-4, 5-dicarboxamide derivatives as jak-2 modulators |
WO2008082487A2 (en) | 2006-12-20 | 2008-07-10 | Schering Corporation | Novel jnk inhibitors |
WO2011026219A1 (en) | 2009-09-01 | 2011-03-10 | Lu qing-bin | Combination therapy for cancer comprising a platinum -based antineoplastic agent and a biocompatible electron donor |
WO2012049277A1 (en) | 2010-10-14 | 2012-04-19 | Proximagen Ltd | Cxcr4 receptor antagonists |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5011451B1 (en) * | 1969-05-05 | 1975-05-01 | ||
GB1363735A (en) * | 1970-10-23 | 1974-08-14 | Hoechst Ag | Process for the manufacture of benzimidazolones |
US3822261A (en) * | 1972-10-30 | 1974-07-02 | Dow Chemical Co | 5,6-dihalo-2-fluoroalkyl-1h-imidazo(4,5-b)pyrazines |
GR72941B (en) * | 1978-10-20 | 1984-01-16 | Lilly Co Eli | |
US4210647A (en) * | 1979-06-18 | 1980-07-01 | Eli Lilly And Company | Antiviral combinations |
JPS597175A (en) * | 1982-07-01 | 1984-01-14 | メルク・エンド・カムパニ−・インコ−ポレ−テツド | Amino and amide derivative of chloronitroamino pyrazine and alkylaminopyrazine useful as additive for radial ray treatment |
GB8722488D0 (en) * | 1987-09-24 | 1987-10-28 | Fujisawa Pharmaceutical Co | Imidazopyridine compound |
WO1994000124A1 (en) * | 1992-06-22 | 1994-01-06 | Eckard Weber | Glycine receptor antagonists and the use thereof |
US5620978A (en) * | 1994-01-03 | 1997-04-15 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon | 8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use thereof as antagonists for the glycine/NMDA receptor |
US5753687A (en) * | 1995-06-19 | 1998-05-19 | Ontogen Corporation | Modulators of proteins with phosphotryrosine recognition units |
EP1254116A4 (en) * | 2000-01-24 | 2003-04-23 | Merck & Co Inc | Alpha v integrin receptor antagonists |
US6538010B1 (en) * | 2000-11-08 | 2003-03-25 | Research Triangle Institute | Compounds and methods for promoting smoking cessation |
CN101155782B (en) * | 2005-04-01 | 2011-05-04 | 大鹏药品工业株式会社 | Potentiator for radiation therapy comprising pyridine derivative as active ingredient |
US20100222345A1 (en) * | 2006-08-09 | 2010-09-02 | Caroline Jean Diaz | Novel compounds as antagonists or inverse agonists for opioid receptors |
RU2011123647A (en) * | 2008-11-10 | 2012-12-20 | Вертекс Фармасьютикалз Инкорпорейтед | COMPOUNDS USEFUL AS ATR KINASE INHIBITORS |
EP2569289A1 (en) * | 2010-05-12 | 2013-03-20 | Vertex Pharmaceuticals Incorporated | Pyrazines useful as inhibitors of atr kinase |
-
2013
- 2013-12-20 KR KR1020157019682A patent/KR102278760B1/en active IP Right Grant
- 2013-12-20 CA CA2895526A patent/CA2895526C/en active Active
- 2013-12-20 CN CN201380073147.7A patent/CN105164107B/en active Active
- 2013-12-20 EP EP13865418.1A patent/EP2935215B1/en active Active
- 2013-12-20 AU AU2013362757A patent/AU2013362757B2/en not_active Ceased
- 2013-12-20 WO PCT/CA2013/051005 patent/WO2014094178A1/en active Application Filing
- 2013-12-20 BR BR112015014855A patent/BR112015014855A2/en not_active Application Discontinuation
- 2013-12-20 US US14/654,165 patent/US9655965B2/en active Active
- 2013-12-20 JP JP2015548130A patent/JP6321673B2/en active Active
- 2013-12-20 MX MX2015008010A patent/MX2015008010A/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006067466A2 (en) | 2004-12-22 | 2006-06-29 | The Wellcome Trust Limited | Pyrazines and pyridines and derivatives thereof as therapeutic compounds |
CA2603810A1 (en) | 2005-04-01 | 2006-10-12 | Taiho Pharmaceutical Co., Ltd. | Potentiator for radiation therapy comprising pyridine derivative as active ingredient |
WO2008042282A2 (en) | 2006-09-28 | 2008-04-10 | Exelixis, Inc. | Imidazole-4, 5-dicarboxamide derivatives as jak-2 modulators |
WO2008082487A2 (en) | 2006-12-20 | 2008-07-10 | Schering Corporation | Novel jnk inhibitors |
WO2011026219A1 (en) | 2009-09-01 | 2011-03-10 | Lu qing-bin | Combination therapy for cancer comprising a platinum -based antineoplastic agent and a biocompatible electron donor |
WO2012049277A1 (en) | 2010-10-14 | 2012-04-19 | Proximagen Ltd | Cxcr4 receptor antagonists |
Non-Patent Citations (51)
Title |
---|
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING COMPANY |
"Handbook of Pharmaceutical Excipients", 2005, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION |
"Pharmaceutical Preformulation and Formulation", 2004, CRC PRESS LLC |
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS |
1984, Database accession no. 5348-42-5 * |
1996, Database accession no. 182631-88-5 * |
2010, Database accession no. 1241725-95-0 * |
A. CHOUDHURY ET AL.: "Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity", MOL CANCER THER, vol. 8, 2009, pages 203 - 2013 |
D. M. REESE: "Anticancer drugs", NATURE, vol. 378, 1995, pages 532 |
DATABASE CAS 1984, Database accession no. 13484-57-6 * |
DATABASE CAS 1984, Database accession no. 1575-37-7 * |
DATABASE CAS 1984, Database accession no. 21304-38-1 * |
DATABASE CAS 1984, Database accession no. 21537-32-6 * |
DATABASE CAS 1984, Database accession no. 21537-33-7 * |
DATABASE CAS 1984, Database accession no. 21537-34-8 * |
DATABASE CAS 1984, Database accession no. 25710-20-7 * |
DATABASE CAS 1984, Database accession no. 33087-39-7 * |
DATABASE CAS 1984, Database accession no. 33848-50-9 * |
DATABASE CAS 1984, Database accession no. 33848-51-0 * |
DATABASE CAS 1984, Database accession no. 38875-53-5 * |
DATABASE CAS 1984, Database accession no. 4 0851-88-5 * |
DATABASE CAS 1984, Database accession no. 40851-95-4 * |
DATABASE CAS 1984, Database accession no. 49764-63-8 * |
DATABASE CAS 1984, Database accession no. 57803-83-5 * |
DATABASE CAS 1984, Database accession no. 68459-98-3 * |
DATABASE CAS 1984, Database accession no. 72435-64-4 * |
DATABASE CAS 1984, Database accession no. 75293-95-7 * |
DATABASE CAS 1984, Database accession no. 76179-43-6 * |
DATABASE CAS 1984, Database accession no. 78582-07-7 * |
DATABASE CAS 1984, Database accession no. 89123-58-0 * |
DATABASE CAS 1984, Database accession no. 95-83-0 * |
DATABASE CAS 1985, Database accession no. 97941-89-4 * |
DATABASE CAS 1990, Database accession no. 129012-04-0 * |
DATABASE CAS 2001, Database accession no. 351447-14-8 * |
DATABASE CAS 2002, Database accession no. 426463-01-6 * |
DATABASE CAS 2005, Database accession no. 857439-62-4 * |
DATABASE CAS 2005, Database accession no. 858241-27-7 * |
DATABASE CAS 2009, Database accession no. 1171836-31-9 * |
DATABASE CAS 2009, Database accession no. 1195519-49-3 * |
DATABASE CAS 2010, Database accession no. 1215698-73-9 * |
DATABASE REGISTRY [online] 16 November 1984 (1984-11-16), XP055263637, retrieved from STN Database accession no. 53338-46-8 * |
DATABASE REGISTRY [online] 17 September 2012 (2012-09-17), XP055263634, retrieved from STN Database accession no. 1394373-23-9 * |
DATABASE REGISTRY [online] 20 April 2010 (2010-04-20), XP055263627, retrieved from STN Database accession no. 1219741-20-4 * |
DATABASE REGISTRY [online] 2007, XP055263632, retrieved from STN Database accession no. 927696-05-7 * |
DATABASE REGISTRY [online] 2011, XP055263638, retrieved from STN Database accession no. 1259479-81-6 * |
DATABASE REGISTRY [online] 24 November 2010 (2010-11-24), XP055263636, retrieved from STN Database accession no. 1254171-36-2 * |
M. D. PRADOS ET AL.: "A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404", INT. J. RADIAT. ONCOL. BIOL. PHYS., vol. 45, 1999, pages 1109 |
P. G. ROSE; B. N. BUNDY; E. B. WATKINS; J. T. THIGPEN; G. DEPPE; M. A. MAIMAN; D. L. CLARKE-PEARSON; S. INSALACO: "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer", N. ENGL. J. MED., vol. 340, 1999, pages 1144 - 53, XP055049677, DOI: doi:10.1056/NEJM199904153401502 |
Q.-B. LU: "Effects of Ultrashort-Lived Prehydrated Electrons in Radiation Biology and Their Applications for Radiotherapy of Cancer", MUTAT. RES.-REV. MUTAT. RES., vol. 704, 2010, pages 190 - 199, XP027045278 |
Q.-B. LU: "Molecular Reaction Mechanisms of Combination Treatments of Low-Dose Cisplatin with Radiotherapy and Photodynamic Therapy", J. MED. CHEM., vol. 50, 2007, pages 2601 - 2604 |
See also references of EP2935215A4 |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015051458A1 (en) | 2013-10-08 | 2015-04-16 | Lu qing-bin | Non-platimun-based anti-cancer compounds for use in targeted chemotherapy |
CN106232581A (en) * | 2013-10-08 | 2016-12-14 | 卢庆彬 | Non-platino anticancer compound for targeted chemotherapy |
AU2014334461B2 (en) * | 2013-10-08 | 2019-06-13 | Qing-bin LU | Non-platinum-based anti-cancer compounds for use in targeted chemotherapy |
US10463662B2 (en) | 2013-10-08 | 2019-11-05 | Qing-Bin Lu | Non-platinum-based anti-cancer compounds for use in targeted chemotherapy |
EP3578176A1 (en) | 2013-10-08 | 2019-12-11 | Lu, Qing-Bin | Non-platinum-based anti-cancer compounds for use in targeted chemotherapy |
CN114380700A (en) * | 2013-10-08 | 2022-04-22 | 卢庆彬 | Non-platinum based anti-cancer compounds for targeted chemotherapy |
US11446294B2 (en) | 2013-10-08 | 2022-09-20 | Qing-Bin Lu | Non-platinum-based anti-cancer compounds for use in targeted chemotherapy |
US11311552B2 (en) * | 2015-04-02 | 2022-04-26 | Proximagen, Llc | Therapies for cancer |
WO2021224186A1 (en) * | 2020-05-04 | 2021-11-11 | Institut Curie | New pyridine derivatives as radiosensitizers |
Also Published As
Publication number | Publication date |
---|---|
EP2935215A4 (en) | 2016-10-26 |
KR20150120953A (en) | 2015-10-28 |
US9655965B2 (en) | 2017-05-23 |
BR112015014855A2 (en) | 2017-07-11 |
CA2895526A1 (en) | 2014-06-26 |
JP2016504325A (en) | 2016-02-12 |
AU2013362757A1 (en) | 2015-07-30 |
KR102278760B1 (en) | 2021-07-20 |
AU2013362757B2 (en) | 2018-06-14 |
US20150343059A1 (en) | 2015-12-03 |
CA2895526C (en) | 2021-08-24 |
JP6321673B2 (en) | 2018-05-09 |
EP2935215B1 (en) | 2019-11-13 |
CN105164107B (en) | 2017-12-05 |
CN105164107A (en) | 2015-12-16 |
EP2935215A1 (en) | 2015-10-28 |
MX2015008010A (en) | 2016-04-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2895526C (en) | Radiosensitizer compounds for use in combination with radiation | |
US11826430B2 (en) | Anti-cancer nuclear hormone receptor-targeting compounds | |
CA2926571C (en) | Non-platinum-based anti-cancer compounds for use in targeted chemotherapy | |
US9750809B2 (en) | Cancer treatment | |
TW202108570A (en) | Anti-cancer nuclear hormone receptor-targeting compounds | |
EP1853243A2 (en) | Treatment of hyperproliferative diseases with anthraquinones |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201380073147.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13865418 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2895526 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2015548130 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14654165 Country of ref document: US Ref document number: MX/A/2015/008010 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015014855 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 20157019682 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013865418 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2013362757 Country of ref document: AU Date of ref document: 20131220 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112015014855 Country of ref document: BR Kind code of ref document: A2 Effective date: 20150619 |