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 action has not yet been elucidated. In this study, we examined the effects of
AGM-1470 on the cell cycle of normal and transformed endothelial cells. We showed that
AGM-1470, at picomolar concentrations, specifically inhibits the proliferation of both bovine aortic endothelial cells and human umbilical vein endothelial cells.
AGM-1470 was ineffective in significantly inhibiting the proliferation of Ea.hy926 cells, a hybrid cell line obtained by the fusion of human umbilical vein endothelial cells with a human
carcinoma cell line, or cEnd.1 cells, a polyoma middle T oncogene-transformed endothelioma cell line derived from mouse embryo. Using a double labeling technique with anti-Ki67
antibodies and
propidium iodide, we demonstrated, with flow cytometry analysis, that
AGM-1470 specifically prevents the entry of endothelial cells into the G1 phase of the cell cycle. We also showed that
AGM-1470 was ineffective in inhibiting endothelial cell migration toward
laminin or capillary-like tube formation inside a
type I collagen matrix induced by
phorbol esters. Our data strongly suggest that
AGM-1470 is a molecule that specifically inhibits a cell cycle control pathway active in normal cells but which could be bypassed or altered in transformed cells.