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The Antiangiogenic Agent Neovastat (Æ-941) Inhibits Vascular Endothelial Growth Factor-mediated Biological Effects¹

Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-UQAM, Centre de Cancérologie Charles-Bruneau, Centre de Recherche de l’Hôpital Ste-Justine, Montréal, Québec, H3T 1C5 Canada [R. B., D. G., S. L., É. B.]; Division of Clinical Sciences, Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [E. A. K., W. D. F.]; Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, J1H 5N4 Canada [P. S., B. S.]; Montreal Heart Institute Research Center, Montréal, Québec H1T 1C8, Canada [M. G. S.]; DBMS/BRCE-EMI 105 CEA, 38054 Grenoble Cedex 9, France [L. T., F. B.]; and Æterna Laboratories, Inc., Québec, Québec, G1P 4P5 Canada [V. D., M-C. P., F. C., I. R., P. P., P. F., E. D.]

Purpose: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, which exerts direct effects on vascular endothelial cells, including endothelial cell proliferation and survival, tubulogenesis, and vascular permeability. In this study, we examined whether Neovastat, a naturally occurring multifunctional antiangiogenic drug, could inhibit the endothelial cell response to VEGF stimulation.

Results: We demonstrated that Neovastat was able to block the VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings, and it also blocked the VEGF-induced endothelial cell tubulogenesis in vitro. In vivo studies showed that Neovastat was able to specifically inhibit VEGF-induced plasma extravasation in numerous tissues, including pancreas and skin. The mechanism of action of Neovastat on VEGF-mediated effects was also evaluated at the molecular level. Neovastat was shown to compete against the binding of VEGF to its receptor in endothelial cells and significantly inhibited the VEGF-dependent tyrosine phosphorylation of VEGF receptor-2, whereas it had no significant effect on VEGF receptor-1 activity. Moreover, the inhibition of receptor phosphorylation was correlated with a marked decrease in the ability of VEGF to induce pERK activation. Neovastat does not compete against the binding of basic fibroblast growth factor, indicating a preferential inhibitory effect on the VEGF receptor.

Conclusions: Because Neovastat was shown previously to inhibit metalloproteinase activities, these results suggest that Neovastat is able to target multiple steps in tumor neovascularization, further emphasizing its use as a pleiotropic, multifunctional antiangiogenic drug.

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