Combination bacteriolytic therapy for the treatment of tumors
Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that spores of anaerobic bacteria in combination with agents which interact with microtubules can cause the destruction of both the vascular and avascular compartments of tumors. Two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxane, docetaxel, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sporulated bacteria. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which spores could germinate. A single intravenous injection of spores plus selected microtubule-interacting agents was able to cause regressions of several tumors in the absence of excessive toxicity.
1. A method for treating a tumor containing one or more poorly vascularized regions in a mammal comprising:
administering to the mammal spores of a toxin-defective, anaerobic bacterium selected from the group consisting of Clostridium novyi and Clostridium sordellii ; and
administering to the mammal one or more taxane microtubule stabilizing anti-tumor agents;
whereby the tumor regresses or its growth is slowed or arrested.
2. The method of claim 1 wherein the anaerobic bacterium is Clostridium novyi.
3. The method of claim 1 wherein the anaerobic bacterium is Clostridium sordellii.
4. The method of claim 1 wherein the spores are administered intravenously.
5. The method of claim 1 wherein the spores are administered intratumorally.
6. The method of claim 1 wherein all or part of a toxin gene of a wild type form of the anaerobic bacterium is deleted.
7. The method of claim 1 wherein the one or more taxanes are selected from the group consisting of taxol, taxotere and MAC-321.
8. The method of claim 7 wherein one of the one or more taxanes is taxotere.
9. The method of claim 7 wherein one of the one or more taxanes is MAC-321.
10. The method of claim 1 further comprising:
administering a nitric oxide synthetase (NOS) inhibitor to the mammal.
11. The method of claim 1 wherein the spores and anti-tumor agent are administered serially.
12. The method of claim 10 wherein the spores, anti-tumor agent and NOS inhibitor are administered serially.