CAPTOPRIL INHIBITS ANGIOGENESIS AND SLOWS THE GROWTH OF EXPERIMENTAL-TUMORS IN RATS

Captopril, an inhibitor of angiotensin converting enzyme, is widely us ed clinically to manage hypertension and congestive heart failure. Her e captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their che motaxis with a biphasic dose-response curve showing an initial decreas e at clinically achievable doses under 10 mu M and a further slow decl ine in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition , but was suppressed by zinc. Direct inhibition by captopril of zinc-d ependent endothelial cell-derived 72- and 92-kD metalloproteinases kno wn to be essential for angiogenesis was also seen. When used systemica lly on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decre asing the number of mitoses present in carcinogen-induced foci of pren eoplastic liver cells and slowing the growth rate of an experimental f ibrosarcoma whose cells were resistant to captopril in vitro. These da ta define this widely used drug as a new inhibitor of neovascularizati on and raise the possibility that patients on long term captopril ther apy may derive unexpected benefits from its antiangiogenic activities.