Current development status of small-molecule vascular disrupting agents.

There is increasing interest in small-molecule drugs that can selectively disrupt the abnormal vasculature associated with disease processes such as cancer and macular degeneration. These agents are distinct from anti-angiogenic strategies, which do not target existing vessels but prevent additional vessel growth, althouglh they may potentially be complimentary with these antiangiogenic strategies. Several vascular disrupting agents (VDAs) are now undergoing clinical evaluation. The main focus of research has been on two drug classes: the first is comprised of agents that bind reversibly with tubulin and prevent microtubule assembly; the second are the flavanoids, which can induce intratumor cytokine release. Data from phase I studies have established that these agents can selectively reduce tumor blood flow at well-tolerated doses. Preclinical data indicate that VDAs can improve the tumor response to cytotoxic chemotherapy, radiation and antiangiogenic treatments. This activity has been attributed to the ability of these agents to selectively destroy the central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. The VDA compounds combretastatin A4 phosphate (CA4P) and 5,6-dimethylxantlenone-4-acetic acid (DMXAA) are being evaluated in phase II clinical trials in combination with conventional cytotoxic therapies for the potential treatment of cancer. This review discusses the small-molecule VDAs in clinical development. In addition, the potential for combination therapy with VDAs and traditional anticancer therapies, such as radiation, chemotherapy and anti-angiogenics is described.