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

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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 k cat 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.

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Authors and Affiliations

  1. Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec, (Canada), H3T 1C5

    Denis Gingras, Dominique Labelle, Carine Nyalendo, Dominique Boivin, Michel Demeule, Chantal Barthomeuf & Richard Béliveau

  2. Laboratoire de Pharmacognosie et Biotechnologies, UMR INSERM U-484, Place H. Dunant, 63001, Clermont-Fd, France

    Chantal Barthomeuf

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  1. Denis Gingras
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  2. Dominique Labelle
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  3. Carine Nyalendo
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  4. Dominique Boivin
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  5. Michel Demeule
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  6. Chantal Barthomeuf
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  7. Richard Béliveau
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Gingras, D., Labelle, D., Nyalendo, C. et al. The Antiangiogenic Agent Neovastat (Æ-941) Stimulates Tissue Plasminogen Activator Activity. Invest New Drugs 22, 17–26 (2004). https://doi.org/10.1023/B:DRUG.0000006171.54078.3d

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  • DOI: https://doi.org/10.1023/B:DRUG.0000006171.54078.3d

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