ANTIANGIOGENESIS BY CYCLOSPORINE

The effects of cyclosporine on certain endothelial cell functions, nam ely matrix metalloprotease (MMP)-2 and MMP-9 secretion, proliferation, chemotaxis, and morphogenesis, were investigated in vitro, and its ef fects on angiogenesis were studied in vivo by using the chick embryo c horioallantoic membrane (CAM) model. In vitro, at low noncytotoxic dos es (2, 4, 8, and 16 mu g/mL), cyclosporine inhibited all these functio ns in a dose-dependent manner, although MMP-2 secretion was inhibited only at 16 mu g/mL. The absence of cytotoxicity was confirmed morpholo gically and also because inhibition was rapidly reversed as soon as cy closporine was removed. In vivo, cyclosporine at 0.012 and 0.024 mu g per CAM displayed noncytotoxic, dose-dependent antiangiogenic activity . Biochemically, the drug inhibited the activity of the endothelial ce ll respiratory chain enzymes succinate oxidase and cytochrome-c oxidas e, again in a dose-dependent manner. This finding could explain the ef fects observed in vitro and in vivo. These antiangiogenic properties o f low-dose cyclosporine warrant further investigation in certain autoi mmune and neoplastic diseases characterized by enhanced angiogenesis.