Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo

Background. Combretastatin A4 Phosphate (CA4P) is a tubulin binding agent w hich causes rapid tumour vascular shutdown. It has anti-proliferative and a poptotic effects on dividing endothelial calls after prolonged exposure, bu t these effects occur on a much longer time scab than the reduction in tumo ur blood flow. This study compared the time course of CA4P effects on endot helial cell shape and reduction in red cell velocity. Methods. Endothelial cell area and Sonn factor (1 - 4 pi x area x perimeter(-2)) were measured f or proliferating and confluent HWECs after CAW treatment. Recovery of shape after CAW and colchicine was compared. Window chamber studies of tumours w ere used to measure led cell velocity. Results 70% reduction in led cell ve locity and 44% reduction in HUVEC form factor occurred by ID minutes. Proli ferating HUVECs underwent greater cell shape change after CA4P, which occur red at lower closes than for confluent cells. Cell shape recovered 24 hours after 30 minutes exposure to CA4P, but not after colchicine. Conclusions- The similar time course of cell shape change and led cell velocity reductio n suggests endothelial cell shape change may be involved early in the in vi vo events Lading to vascular shutdown. Differences in the recovery fram the shape changes induced by CA4P and colchicine could underlie the different toxicity profiles of these drugs.