Targeting Vascular and Avascular Compartments of Tumors withC. novyi-NTand Anti-microtubule Agents

Abstract

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 C. novyi-NT in combination with anti-microtubule agents can cause the destruction of both the vascular and avascular compartments of tumors. The two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with C. novyi-NT. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by C. novyi-NT. 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 C. novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity.

A Novel Anti-Vascular Therapy for Cancer

“…The growth of these bacteria in hypoxic areas of the tumor, presumably killed tumor cells, but could also have caused apoptosis of residual endothelial cells, possibly by induction of tumor necrosis factor alpha (TNF-α), or by other locally active toxins made by C. novyi-NT. 17 In addition to the new mechanisms on anti-microtubule agents provided by this report, and on the synergy of bacteriolytic therapy with these agents, the experiments described by Dang et al 1 have important clinical implications. For certain inoperable bulky tumors such as in the brain, liver or colon, it would be important to avoid rapid necrosis, possibly by decreased dosing of the microtubule regulators spread out over time.…”

“…Dang et al of the Vogelstein laboratory, report the development of a novel form of experimental anti-vascular therapy for cancer. 1 In mice bearing large tumors, a single intravenous dose of spores of a strict anaerobic bacterium was administered in combination with a single dose of either microtubule destabilizing or stabilizing molecules. This regimen caused tumor regression and cured a significant number of mice.…”

“…Dang et al 1 appear to have circumvented the peripheral neovascularization problem by combining anti-vascular therapy with administration of anaerobic bacterial spores. The growth of these bacteria in hypoxic areas of the tumor, presumably killed tumor cells, but could also have caused apoptosis of residual endothelial cells, possibly by induction of tumor necrosis factor alpha (TNF-α), or by other locally active toxins made by C. novyi-NT.…”

“…For example, ultralow doses of paclitaxel inhibit angiogenesis in vitro. 13 Dang et al 1 emphasize that concomitant administration of inhibitors of nitric oxide synthesis enhance the response to lower doses of microtubule destabilizers. Because endostatin inhibits endothelial nitric oxide synthesis (eNOS), 14 it may possibly be synergistic with the anti-vascular therapy reported here.…”

“…The anti-vascular therapy reported by Dang et al 1 may also be useful in certain nonneoplastic diseases such as large endangering lymphatic vascular malformations which often recur after attempts at intraluminal sclerosis, or after surgical excision. The lymph fluid in these large lymphatic malformations may be sufficiently low in oxygen that intraluminal bacteriolytic therapy plus anti-microtubule therapy could be tested as an initial treatment.…”