Combretastatin A4 phosphate: background and current clinical status.

Combretastatin A4 phosphate (CA4P) represents the lead compound in a group of novel tubulin depolymerising agents being developed as vascular targeting agents (VTAs). VTAs are drugs that induce rapid and selective vascular dysfunction in tumours. CA4P is a water-soluble prodrug of the cis-stilbene CA4 originally isolated from the tree Combretum caffrum. Preclinical studies have shown that CA4P induces blood flow reductions and subsequent tumour cell death in a variety of preclinical models. Moreover, this activity has been linked to its ability to rapidly alter the morphology of immature endothelial cells by disrupting their tubulin cytoskeleton. Phase I clinical trials have established a maximum tolerated dose in the range 60-68 mg/m2 and in addition have established that significant changes to tumour perfusion can be achieved across a wide range of doses. The dose-limiting toxicities include tumour pain, ataxia and cardiovascular changes. The maximum tolerated dose was independent of schedule, indicating the absence of cumulative toxicity. Although unexpected from preclinical studies, some evidence of clinical response was seen using CA4P as a single modality. Based on the Phase I data, combination studies of CA4P with established therapies are in progress and should determine whether the exciting preclinical data obtained when VTAs are used in combination with cytotoxic chemotherapy, radiation, radioimmunotherapy and even antiangiogenic agents, can be translated into man.