Disrupting established tumor blood vessels

Abstract

The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular‐targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor‐vascular disrupting agents (tumor‐VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor‐VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin‐binding compounds. ASA404, of the flavonoid class, is the most advanced tumor‐VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor‐VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies. Cancer 2010. © 2010 American Cancer Society.Selectively targeting tumor vasculature with tumor‐vascular disrupting agents (tumor‐VDAs) represents a promising and innovative approach to improving the efficacy of standard anticancer therapies. Phase 2 clinical trials with the flavonoid tumor‐VDA ASA404 have demonstrated activity, including an apparent survival advantage, from combination therapy in patients with nonsmall cell lung cancer. Phase 3 trials are ongoing.