AGM-1470, A POTENT ANGIOGENESIS INHIBITOR, PREVENTS THE ENTRY OF NORMAL BUT NOT TRANSFORMED ENDOTHELIAL-CELLS INTO THE G(1) PHASE OF THE CELL-CYCLE

AGM-1470 is a potent angiogenesis inhibitor that is very effective in inhibiting endothelial cell proliferation in both in vitro and in vivo models and that prevents tumor growth in vivo. Although this molecule appears to be a most promising anticancer drug, its mechanism of acti on has not yet been elucidated. In this study, we examined the effects of AGM-1470 on the cell cycle of normal and transformed endothelial c ells. We showed that AGM-1470, at picomolar concentrations, specifical ly inhibits the proliferation of both bovine aortic endothelial cells and human umbilical vein endothelial cells. AGM-1470 was ineffective i n significantly inhibiting the proliferation of Ea.hy926 cells, a hybr id cell line obtained by the fusion of human umbilical vein endothelia l cells with a human carcinoma cell line, or cEnd.1 cells, a polyoma m iddle T oncogene-transformed endothelioma cell line derived from mouse embryo. Using a double labeling technique with anti-Ki67 antibodies a nd propidium iodide, we demonstrated, with flow cytometry analysis, th at AGM-1470 specifically prevents the entry of endothelial cells into ghe G1 phase of the cell cycle. We also showed that AGM-1470 was ineff ective in inhibiting endothelial cell migration toward laminin or capi llary-like tube formation inside a type I collagen matrix induced by p horbol esters. Our data strongly suggest that AGM-1470 is a molecule t hat specifically inhibits a cell cycle control pathway active in norma l cells but which could be bypassed or altered in transformed cells.