Investigational New Drugs

, Volume 22, Issue 1, pp 17–26

The Antiangiogenic Agent Neovastat (Æ-941) Stimulates Tissue Plasminogen Activator Activity

  • Denis Gingras
  • Dominique Labelle
  • Carine Nyalendo
  • Dominique Boivin
  • Michel Demeule
  • Chantal Barthomeuf
  • Richard Béliveau
Article

DOI: 10.1023/B:DRUG.0000006171.54078.3d

Cite this article as:
Gingras, D., Labelle, D., Nyalendo, C. et al. Invest New Drugs (2004) 22: 17. doi:10.1023/B:DRUG.0000006171.54078.3d

Abstract

The plasminogen activator/plasmin system represents a key component of the proteolytic machinery underlying angiogenesis. In this work, we investigated the effect of Neovastat (Æ-941), a naturally occurring multifunctional antiangiogenic agent that is currently in Phase III clinical trials, on tissue and urokinase plasminogen activator activities. We found that in vitro, Neovastat at 100μg/ml markedly stimulates t-PA-mediated plasmin generation, while it slightly inhibits the generation of plasmin mediated by uPA. The stimulatory effect of Neovastat on t-PA activity was markedly increased by a heat treatment, resulting in a 15-fold increase in the rate of activation of plasminogen. Neovastat did not directly stimulate the activity of t-PA or plasmin towards exogenous substrates, suggesting that its effect requires the presence of plasminogen. Accordingly, kinetic analysis showed that Neovastat increases both the kcat of t-PA as well as its affinity for plasminogen by 10-fold. The stimulation of t-PA activity by Neovastat was also correlated with a direct interaction of Neovastat with plasminogen as monitored by the surface plasmon resonance technology. Overall, these results identify Neovastat as a potent stimulator of t-PA-dependent activation of plasminogen, further emphasizing its pleiotropic mechanism of action on several molecular events involved in angiogenesis.

Neovastat Æ-941 angiogenesis t-PA endothelial cells 

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Denis Gingras
    • 1
  • Dominique Labelle
    • 1
  • Carine Nyalendo
    • 1
  • Dominique Boivin
    • 1
  • Michel Demeule
    • 1
  • Chantal Barthomeuf
    • 1
    • 2
  • Richard Béliveau
    • 1
  1. 1.Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-BruneauCentre de Recherche de l'Hôpital Ste-JustineMontréal(Canada)
  2. 2.Laboratoire de Pharmacognosie et BiotechnologiesUMR INSERM U-484Clermont-FdFrance