Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate

Combretastatin A4 phosphate has recently been identified by us as an agent which can selectively damage tumour neovasculature. In the current study we establish that combretastatin induces extensive blood flow shutdown in the tumour compared to normal tissues. Histological assessment of vascular shutdown shows that over 90% of vessels are rendered non-functional 6 hrs post-treatment with 100 mg/kg i.p. Measurement of blood flow using a diffusible tracer 86RbCl indicates an overall reduction in perfusion by only 50-60%. This discrepancy probably reflects increased blood flow in the normal tissue vasculature supplying the tumour rim, which is caused by the ischaemia-induced release of vasoactive mediators. The vascular shutdown induced by administration of 100 mg/kg of combretastatin A4 phosphate results in extensive cell loss in the 24 hrs following treatment, however this is not translated into any significant effect on tumour growth. The continued growth of the tumour is attributed to an actively proliferating population of cells at the periphery of the tumour, which are dependent on normal tissue vasculature for their survival. We have attempted to target this residual population by combining combretastatin A4 phosphate with cytotoxic approaches. Cis platinum and radiation have been used. The results show that combretastatin can significantly enhance tumour response to both cis platinum and radiation. In summary, the studies confirm combretastatin A4 phosphate as a novel agent which targets and damages tumour vasculature and, moreover, indicate its potential therapeutic usefulness as an adjuvant to conventional cytotoxic approaches.