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Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels

¹ Department of Anatomy, ² Cardiovascular Research Institute, Comprehensive Cancer Center, University of California, San Francisco, California; and ³ The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Donald M. McDonald, University of California, San Francisco, 513 Parnassus Avenue, S1363, San Francisco, CA 94143-0452. Phone: 415-476-6616; Fax: 415-476-4845; E-mail: dmcd{at}itsa.ucsf.edu.

Tumor blood vessels normalized by antiangiogenic therapy may provide improved delivery of chemotherapeutic agents during a window of time but it is unknown how protein expression in tumor vascular endothelial cells changes. We evaluated the distribution of RGD-4C phage, which binds _vß₃, _vß₅, and ₅ß₁ integrins on tumor blood vessels before and after antiangiogenic therapy. Unlike the control phage, fd-tet, RGD-4C phage homed to vascular endothelial cells in spontaneous tumors in RIP-Tag2 transgenic mice in a dose-dependent fashion. The distribution of phage was similar to _vß₃ and ₅ß₁ integrin expression. Blood vessels that survived treatment with AG-013736, a small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, had only 4% as much binding of RGD-4C phage compared with vessels in untreated tumors. Cellular distribution of RGD-4C phage in surviving tumor vessels matched the ₅ß₁ integrin expression. The reduction in integrin expression on tumor vessels after antiangiogenic therapy raises the possibility that integrin-targeted delivery of diagnostics or therapeutics may be compromised. Efficacious delivery of drugs may benefit from identification by in vivo phage display of targeting peptides that bind to tumor blood vessels normalized by antiangiogenic agents. (Cancer Res 2006; 66(5): 2639-49)

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