ASA404: a tumor vascular-disrupting agent with broad potential for cancer therapy.

ASA404 (5,6-dimethylxanthenone-4-acetic acid) was developed as an analogue of flavone acetic acid and found to induce hemorrhagic necrosis of experimental tumors. ASA404 simultaneously targets at least two cell types - vascular endothelial cells and macrophages - within the tumor microenvironment. In murine tumors, ASA404 induces coordinated decreases in tumor blood flow, increases in vascular permeability and increases in vascular endothelial apoptosis, all occurring within 1 h of administration. Over a slightly longer time scale, ASA404 induces an increase in tumor concentrations of TNF and a number of other cytokines. Phase I clinical trials confirmed its vascular effects in humans and Phase II trials demonstrated its activity in combination with the cytotoxic agents carboplatin and paclitaxel. While the molecular target of its action is not yet identified, current results suggest that ASA404 has the potential to augment the antitumor effects of other agents in cancer treatment. Studies of changes in tumor tissue following treatment with ASA404 either alone or combined and other agents will provide new insights into the dynamics of the tumor microenvironment.