title: The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
authors.forename: Denis
authors.initials: D
authors.lastname: Gingras
authors.forename: Erwin A
authors.initials: EA
authors.lastname: Kruger
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lamy
authors.forename: Pierre
authors.initials: P
authors.lastname: Sirois
authors.forename: Bryan
authors.initials: B
authors.lastname: Simard
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sirois
authors.forename: Leone
authors.initials: L
authors.lastname: Tranqui
authors.forename: Fabienne
authors.initials: F
authors.lastname: Baffert
authors.forename: Edith
authors.initials: E
authors.lastname: Beaulieu
authors.forename: Violetta
authors.initials: V
authors.lastname: Dimitriadou
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Pépin
authors.forename: Frank
authors.initials: F
authors.lastname: Courjal
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ricard
authors.forename: Patrick
authors.initials: P
authors.lastname: Poyet
authors.forename: Pierre
authors.initials: P
authors.lastname: Falardeau
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Eric
authors.initials: E
authors.lastname: Dupont
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000254:growth & development; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002199:Capillary Permeability / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008222:Lymphokines / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D014020:Tissue Extracts / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D014020:Tissue Extracts; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C111481:shark cartilage extract; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor