The development of the tumor vascular-disrupting agent ASA404 (vadimezan, DMXAA): current status and future opportunities.
BACKGROUND
Targeting tumor vasculature with antiangiogenic agents improves outcomes achieved with chemotherapy in some cancers, but toxicity limits their applicability. Tumor vascular-disrupting agents (tumor-VDAs) induce an acute collapse in tumor vascular supply; ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid [DMXAA]) is the tumor-VDA most advanced in clinical development. Recent randomized trials of ASA404 in combination with chemotherapy suggested a survival advantage in NSCLC comparable to that achieved with bevacizumab, but with little additional toxicity. Phase III trials in advanced NSCLC have completed accrual, and a review of this exciting agent is timely.


METHODS
This review focuses on the development of ASA404 to date, its mechanisms of action, the current body of clinical research and potential avenues for therapeutic use. It includes all completed clinical trials since it entered clinical testing in 1995 through to 2009.


RESULTS
This review will help the reader to understand why ASA404 is unique among tumor-VDAs; the clinical trial methodology required to evaluate such agents; and its remarkable potential clinical utility.


CONCLUSIONS
ASA404 is a tumor-VDA that offers considerable potential to improve outcomes in cancer patients in combination with existing treatments.
Head
Michelle
M
Waikato Hospital, Regional Cancer Centre, Waikato Hospital, Private Bag 3200, Hamilton 3240, New Zealand.
Jameson
Michael B
MB
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D044004:Xanthones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan