Combination antitumor therapy
View Patent ↗The present disclosure relates to methods of treating cancers that are responsive to antimetabolite or antimitotic anti-cancer agents. The methods involve the use of at least one anti-cancer agent selected from antimetabolite anti-cancer agents, antimitotic anti-cancer agents, and combinations thereof, and a superoxide dismutase mimetic to potentiate the therapeutic effect of the anti cancer agent(s).
1. A method of treating a cancer that is responsive to an antimetabolite or antimitotic anti-cancer agent in a mammalian subject afflicted with the cancer, the method comprising:
administering to the subject at least one anti-cancer agent selected from antimetabolite anti-cancer agents, antimitotic anti-cancer agents, and combinations thereof, and a selective superoxide dismutase mimetic to potentiate the therapeutic effect of the anti-cancer agent(s); wherein
the antimetabolite anti-cancer agent is selected from the group consisting of 2-fluorodeoxycytidine, 3′-azido-3′-deoxythymidine, 3′-deoxy-3′-deoxythymidin-2′-ene, 3′-dideoxycytidin-2′-ene, 3-fluoro-3′-deoxythymidine, 5-fluorocytosine, 5-fluorouracil, 5-methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, 6-azauridine, 6-mercaptopurine, 8-aza-adenosine, 8-aza-guanosine, 8-fluoro-adenosine, acyclovir, allopurinol, ancitabine, arabinosyl adenine, azacitidine, azathiprine, bromouracil, capecitabine, carmofur, chlorouracil, cladribine, cytarabine, cytosine arabinoside, denopterin, deoxycoformycin, dideoxyuridine, dihydrouracil, doxifluridine, enocitabine, floxuridine, fludarabine, gancylovir, gemcitabine, methotrexate, pemetrexed, pentostatin, pteropterin, raltitrexed, thiamiprine, thioguanine, trimetrexate, salts thereof, and combinations thereof;
the antimitotic anti-cancer agent is selected from the group consisting of docetaxel, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine, salts thereof, and combinations thereof;
wherein the selective superoxide dismutase mimetic has no significant activity toward hydrogen peroxide and corresponds to Formula (4419):
wherein X and Y are ligands.
2. The method of claim 1 wherein X and Y are chloro.
3. The method of claim 1 wherein the antimetabolite anti-cancer agent is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, salts thereof, and combinations thereof.
4. The method of claim 1 wherein the anti metabolite anti-cancer agent is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, salts thereof, and combinations thereof.
5. The method of claim 1 wherein the antimetabolite anti-cancer agent is a pyrimidine analog other than 5-fluorouracil.
6. The method of claim 1 wherein the antimetabolite anti-cancer agent is gemcitabine or a salt thereof.
7. The method of claim 1 wherein the antimetabolite anti-cancer agent is gemcitabine HCl.
8. The method of claim 1 wherein the anti-cancer agent(s) and the superoxide dismutase mimetic are administered simultaneously.
9. The method of claim 1 wherein the anti-cancer agent(s) and the superoxide dismutase mimetic are administered in sequence.
10. The method of claim 1 wherein the anti-cancer agent(s) is/are administered prior to administration of the superoxide dismutase mimetic.
11. The method of claim 1 wherein the anti-cancer agent(s) is/are administered at least 1 hour, but no more than three days, after administration of the superoxide dismutase mimetic.
12. The method of claim 1 wherein the anti-cancer agent(s) is/are administered within 24 hours after administration of the superoxide dismutase mimetic.
13. The method of claim 1 wherein the superoxide dismutase mimetic is administered within at least 1 plasma half-life of the anti-cancer agent(s), but no more than 4 plasma half-lives of the anti-cancer agent(s).
14. A method of treating a cancer that is responsive to an antimetabolite anti-cancer agent in a mammalian subject afflicted with the cancer, the method comprising:
administering to the subject at least one antimetabolite anti-cancer agent selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, salts thereof, and combinations thereof, and a selective superoxide dismutase mimetic to potentiate the therapeutic effect of the anti-cancer agent(s); wherein
the selective superoxide dismutase mimetic has no significant activity toward hydrogen peroxide and corresponds to Formula (4419):
wherein X and Y are ligands.
15. The method of claim 14 wherein the antimetabolite anti-cancer agent is gemcitabine or a salt thereof.
16. The method of claim 15 wherein X and Y are chloro.
17. The method of claim 14 wherein the antimetabolite anti-cancer agent is gemcitabine HCl.
18. The method of claim 14 wherein the anti-cancer agent(s) is/are administered prior to administration of the superoxide dismutase mimetic.
19. A method of treating a cancer that is responsive to an antimitotic anti-cancer agent in a mammalian subject afflicted with the cancer, the method comprising:
administering to the subject at least one antimitotic anti-cancer agent selected from the group consisting of docetaxel, paclitaxel, salts thereof, and combinations thereof, and a selective superoxide dismutase mimetic to potentiate the therapeutic effect of the anti-cancer agent(s); wherein
the selective superoxide dismutase mimetic has no significant activity toward hydrogen peroxide and corresponds to Formula (4419):
wherein X and Y are ligands.
20. The method of claim 19 wherein the antimitotic anti-cancer agent is paclitaxel.
21. The method of claim 20 wherein X and Y are chloro.
22. The method of claim 19 wherein the anti-cancer agent(s) is/are administered prior to administration of the superoxide dismutase mimetic.