Temporal aspects of the action of ASA404 (vadimezan; DMXAA)

Tumor vascular disrupting agents (tumor VDAs) act by selective induction of tumor vascular failure. While their action is distinct from that of antiangiogenic agents, their clinical potential is likely to reside in improving the efficacy of combination therapy.

This review describes the preclinical development, clinical trial and mode of action of ASA404, a flavonoid class tumor VDA. This class has a unique dual action, simultaneously disrupting vascular endothelial function and stimulating innate tumor immunity. This review covers the early development of ASA404, through to Phase III trial.

The reader will gain insight into the sequence of ASA404-induced changes in tumor tissue. Early events include increased vascular permeability, increased endothelial apoptosis and decreased blood flow, while later effects include the induction of serotonin, tumor necrosis factor, other cytokines and chemokines, and nitric oxide. This cascade of events induces sustained reduction of tumor blood flow, induction of tumor hypoxia and increased inflammatory responses. The reader will also gain an appreciation of how the potentiation of radiation and chemotherapeutic effects by ASA404 in murine tumors shaped the development of combination clinical trials.

Although there are species differences in ASA404 activity, many features of its action in mice translate to human studies. The future of ASA404 as an effective clinical agent will rely on the development of an appreciation of its ability to optimize the complex interaction between tumor vasculature and tumor immunity during therapy.