Potent anti-metastatic activity of combretastatin-A4

The requirement for tumour vascularisation to permit the expansion of solid tumours beyond a threshold size of approximately I mm diameter has focusse d attention on anti-vascular and anti-angiogenic agents for cancer therapy. Combretastatin-A4 (cis CA-4P) is a tubulin-binding agent that is cytotoxic for proliferating endothelial cells in vitro and causes anti-vascular effe cts in the established tumour vessels of some primary tumours. Preliminary data from Phase I clinical trials indicate that cis CA-4 may also be effect ive in targeting the vasculature of human tumours. As metastatic disease is the principal cause of mortality in cancer, we have investigated the effec ts of cis CA-4 on metastatic development using an in vivo model. We show th at bolus or continuous administration of cis CA-4P results in potent inhibi tion of metastases derived from ectopic primary Lewis lung carcinomas in mi ce whereas the trans CA-4 isomer is without effect. These data further char acterise the activity of CA-4 in vivo and suggest that the drug should be e valuated clinically as an anti-metastatic agent.