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 undergoi ng Phase 1 clinical trial in the USA and UK: Its mechanism of action is tho ught to be related to tubulin-binding properties that result in rapid, tumo ur endothelial cell damage, neovascular shutdown and subsequent haemorrhagi c 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 refractor y marine colon adenocarcinoma but the damage was not accompanied by any mea surable effect on tumour growth. Tumours continued to grow from the viable rim that remained. Combination chemotherapy with 5- fluorouracil (5-FU) res ulted in significant (p<0.01) anti-tumour effects. Measurement of 5-FU conc entrations suggested that this was true synergism and not simply a pharmaco kinetic interaction due to the vascular mechanism of combA-4P. The study su ggests that if an antivascular mechanism can be demonstrated in humans, com bination chemotherapy should be rapidly assessed in a clinical setting.