Small Molecule Vascular Disrupting Agents: Potential New Drugs for Cancer Treatment, a 2009 Update

Vascular disrupting agents (VDAs) are a new class of potential anticancer drugs that selectively destroy tumor vasculature and shutdown blood supply to solid tumors, causing extensive tumor cell necrosis. VDAs target established tumor blood vessels, which are distinct from antiangiogenic agents that prevent the formation of new blood vessels. There are two types of VDAs, small molecules and ligand-directed agents. Most of the small molecule VDAs are tubulin inhibitors, including CA4P, ZD6126, AVE8062, OXi-4503, NPI-2358, MN-029, EPC2407, CYT997, MPC-6827, ABT-751 and TZT-1027. The others are synthetic flavonoids including FAA and DMXAA that induce the production of local cytokines such as TNF-alpha. VDAs have shown good antitumor efficacy in animal models, especially in combination with established anticancer agents. Several VDAs, including CA4P and DMXAA, have demonstrated good safety profile as well as some promising efficacy in phase I and II clinical trials. Currently CA4P, DMXAA and AVE8062 are in phase III clinical trials, NPI-2358, CYT997, MPC-6827 and ABT-751 are in phase II clinical trials, and OXi-4503 and EPC2407 are in phase I clinical trials. This review will focus on recent progress in the discovery and development of small molecule VDAs, including recently published patent applications and issued patents related with small molecule VDAs.

Keywords: Vascular disrupting agents (VDAs), anticancer drugs, small molecule, tubulin inhibitors, synthetic flavonoids, CA4P, DMXAA, ZD6126, AVE8062, OXi-4503, MN-029, NPI-2358, EPC2407, CYT997, MPC-6827, ABT-751 and TZT-1027