IFN-β-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

By attacking established tumor vasculature, vascular disrupting agents (VDAs) represent an alternative approach to the treatment of cancer. One such VDA, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), is scheduled for phase III trials for prostate and lung cancer in combination with conventional chemotherapies. In this work, we identify interferon-beta (IFN-beta) as a central mediator in the host's response to DMXAA. In mice bearing Lewis lung adenocarcinomas, a single intraperitoneal dose of DMXAA was shown to effect a highly significant reduction in tumor growth rate in wild-type mice that was not seen in IFN-beta-null mice. Moreover, intratumoral cytokine expression was shown to be dependent on host-derived IFN-beta, as DMXAA-treated IFN-beta- null mice demonstrated a lack of induction of not only IFN-beta but also the antiangiogenic cytokine, IP-10, in excised tumor tissue. These results support the conclusion that DMXAA derives its potent anticancer properties in part through elicitation of IFN-beta expression by host-derived elements.