Antiangiogenesis is produced by nontoxic doses of vinblastine

The effects of vinblastine (VBL) on endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, spreading on fibronectin (F N), secretion of matrix-metalloproteinase-2 (MMP-2) and MMP-9, and morphoge nesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (C AM) model. In vitro, at noncytotoxic doses (0.1, 0.25, 0.5, 0.75, and 1 pmo l/L), VBL impacted all these functions, except secretion of MMPs, in a dose -dependent fashion. By contrast, proliferation of other primary cells such as fibroblasts and lymphoid tumor cells was not impacted. In vivo, VBL at 0 .5, 0.75, and 1 pmol/L again displayed a dose-dependent antiangiogenic acti vity. Lack of cytotoxicity in vitro and in vivo was shown both morphologica lly, and also because the antiangiogenic effects were rapidly abolished whe n VBL was removed. Apoptosis was not induced. At the ultrastructural level, impairment of cell functions in vitro was associated with thin disturbance of the cytoskeleton, in the form of slight depolymerization and accumulati on of microfilaments, which was equally reversible. Results suggest that VB L has an antiangiogenic component at very low, noncytotoxic doses, and that antiangiogenesis by VBL could be used to treat a wide spectrum of angiogen esis-dependent diseases, including certain chronic inflammatory diseases, K aposi's sarcoma, and cancer. (C) 1999 by The American Society of Hematology .