Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

• DOI: 10.1073/pnas.0807055105
• Publication Date: 2008-09-26T00:44:16Z
• Authors: Hans Petter Eikesdal; Hikaru Sugimoto; Gabriel Birrane; Yohei Maeshima; Vesselina G. Cooke; Mark Kieran; Raghu Kalluri
• Keywords: Angiogenesis inhibitor

Tumstatin is an angiogenesis inhibitor that binds to αvβ3 integrin and suppresses tumor growth. Previous deletion mutagenesis studies identified a 25-aa fragment of tumstatin (tumstatin peptide) with in vitro antiangiogenic activity. Here, we demonstrate systemic administration this peptide inhibits growth angiogenesis. Site-directed amino acids L, V, D as essential for the activity tumstatin. The on proliferating endothelial cells localizes select endothelium vivo . Using 3D molecular modeling, identify putative interaction interface integrin. antitumor peptide, combination bevacizumab (anti-VEGF antibody), displays significant improvement efficacy against human renal cell carcinoma xenografts when compared single-agent use. Collectively, our results specifically endothelium, its action mediated by integrin, and, anti-VEGF antibody it exhibits enhanced suppression carcinoma.