Addition of integrin binding sequence to a mutant human endostatin improves inhibition of tumor growth

Authors

  • Yumi Yokoyama,

    1. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
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  • S. Ramakrishnan

    Corresponding author
    1. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
    2. Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis, MN, USA
    3. Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN, USA
    • Department of Pharmacology, 6-120 Jackson Hall, 321 Church Street, S.E., University of Minnesota, Minneapolis, MN 55455
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Abstract

Tumor vasculatures express high levels of αVβ3Vβ5 and α5β1 integrins. Consequently, peptides containing the RGD (Arg-Gly-Asp) sequence, which is present in ligands of integrins, is effective in targeting therapeutic reagents to tumor vascular endothelium. In our study, we investigated whether the biologic activity of endostatin can be enhanced by the addition of an integrin targeting sequence. RGD sequence was added to either the amino or carboxyl terminus of endostatin containing a point mutation, P125A-endostatin. Earlier we have shown that the P125A mutation did not affect the biologic activity of endostatin but in fact had better antiangiogenic activity when compared to the native molecule. Further modification of P125A-endostatin with the RGD motif showed specific and increased binding to endothelial cells, and the increased binding coincided with improved antiangiogenic properties. Both amino and carboxyl terminal RGD-modification of P125A-endostatin resulted in greater inhibition of endothelial cell migration and proliferation. RGD modification increased tumor localization without affecting the circulatory half-life of P125A-endostatin, and RGD-modified P125A-endostatin was found to be more effective when compared to the P125A-endostatin in inhibiting ovarian and colon cancer growth in athymic mice. Complete inhibition of ovarian tumor growth was observed when P125A-endostatin-RGD was encapsulated into alginate beads. These studies demonstrate that addition of a vascular targeting sequence can enhance the biologic activity of an antiangiogenic molecule. © 2004 Wiley-Liss, Inc.

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