Plant-derived vascular disrupting agents: compounds, actions, and clinical trials

The tumor vasculature of solid tumors offers unique characteristics compared to the normal vasculature and, therefore, represents an attractive target in anti-cancer therapy. Besides the classic anti-angiogenic agents, which inhibit tumor neovascularization, a novel promising class of anti-tumor drugs has emerged in the last years, the vascular-disrupting agents (VDAs). In contrast to angiogenesis inhibitors, VDAs act on already established tumor blood vessels of large solid tumors and induce a vascular shutdown by targeting tumor endothelial cells. This results in extensive necrotic tumor cell death. The sources of VDAs are quite divers, however, the plant-derived compounds represent the largest and most prominent class. Plant-derived VDAs have undergone extensive preclinical investigations and are now tested in several advanced clinical trials. In this review we summarize preclinical data, including drug-target relationships as well as functional in vitro and in vivo assays, discuss their molecular way of action, and update the clinical status of the most prominent plant-derived VDAs: FAA/DMXAA, CA-4-P, OXi4503, AVE8062, and ZD6126. All these data emphasize the value of secondary plant metabolites and their (semi-)synthetic derivatives for current drug discovery.