SURAMIN IS A POTENT INHIBITOR OF VASCULAR ENDOTHELIAL GROWTH-FACTOR -A CONTRIBUTION TO THE MOLECULAR-BASIS OF ITS ANTIANGIOGENIC ACTION

Vascular Endothelial Growth Factor (VEGF) is a specific endothelial mi togen and an important angiogenic factor in vivo, capable of inducing therapeutic angiogenesis when administered to ischemic myocardium, Sur amin, originally developed as an anti-trypanosomal agent, was recently shown to exert an antiangiogenic action, We have tested the hypothesi s, whether the antiangiogenic effect of suramin may be mediated via in hibition of VEGF function. Using cultured endothelial cells and a [H-3 ]thymidine incorporation assay, we were able to show, that the action of VEGF upon mitogenicity is inhibited by suramin in a dose-dependent manner. The same was true for inhibition of VEGF-induced chemotaxis of endothelial cells. Suramin inhibited VEGF-inducible tyrosine phosphor ylation of KDR as determined by in vitro kinase assay. Moreover, suram in was shown to inhibit VEGF-induced tyrosine phosphorylation of KDR i n intact cells, indicating an interaction of suramin with the VEGF-rec eptor KDR as the cause of its inhibitory activity. The antiangiogenic effect of suramin may be mediated-at least in part-by inhibition of VE GF function, Given the feasibility of in vivo use, suramin may be a va luable tool for investigating the functional role of angiogenesis in t he cardiovascular system. (C) 1996 Academic Press Limited.