Colchicine Site Inhibitors of Microtubule Integrity as Vascular Disrupting Agents

Drugs that bind to the colchicine binding site of tubulin and induce tubulin depolymerization hold promise as antitumor drugs through their ability to induce cell cycle arrest and to kill cancer cells through apoptosis and mitotic catastrophe. However, development of this group of compounds as direct antitumor cytotoxic agents has not proved successful. Over the last few years, the potential of these compounds to act as selective vascular disrupting agents has been recognized. Several agents have advanced to phase I and phase II clinical studies, and their capacity to suppress growth of the tumor vasculature has been confirmed. Toxicity in terms of cardiovascular and thromboembolic events remains a major concern and their therapeutic efficacy as single agents has been disappointing. Nevertheless, a more comprehensive understanding of tumor compensatory mechanisms and potential combination strategies with anti-angiogenic agents Suggest that vascular targeting therapy may be a fruitful direction for the further development of this class of drugs as anticancer agents. Drug Dev Res 69: 352-358, 2008. (c) 2008 Wiley-Liss, Inc.