Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma

The di-sodium phosphate pro-drug of combretastatin-A4(combA-4P) is undergoing Phase 1 clinical trial in the USA and UK. Its mechanism of action is thought to be related to tubulin-binding properties that result in rapid, tumour endothelial cell damage, neovascular shutdown and subsequent haemorrhagic necrosis. Drugs that work by this mechanism are unlikely to eradicate the tumour as a single agent but should potentiate standard chemotherapy. This study demonstrates that extensive necrosis occurred in a treated refractory murine colon adenocarcinoma but the damage was not accompanied by any measurable effect on tumour growth. Tumours continued to grow from the viable rim that remained. Combination chemotherapy with 5-fluorouracil (5-FU) resulted in significant (p < 0.01) anti-tumour effects. Measurement of 5-FU concentrations suggested that this was true synergism and not simply a pharmacokinetic interaction due to the vascular mechanism of combA-4P. The study suggests that if an antivascular mechanism can be demonstrated in humans, combination chemotherapy should be rapidly assessed in a clinical setting.