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Inhibition of _vß₃ Integrin Survival Signaling Enhances Antiangiogenic and Antitumor Effects of Radiotherapy

Authors' Affiliations: Departments of ¹ Radiation Oncology and ² Pathology, German Cancer Research Center, Heidelberg, Germany; ³ Pfizer Global Research and Development, Chesterfield, Missouri; ⁴ SUGEN, Inc., South San Francisco, California; ⁵ Department of Radiation Oncology, The Vanderbilt Clinic, Vanderbilt University, Nashville, Tennessee; and ⁶ Department of Immunology, The Scripps Research Institute, La Jolla, California

Requests for reprints: Peter E. Huber, Department of Radiation Oncology, German Cancer Research Center (DKFZ), 280 Im Neuenheimer Feld, 69120 Heidelberg, Germany. Phone: 49-6221-42-2515; Fax: 49-6221-42-2514; E-mail: p.huber{at}dkfz.de.

The involvement of _vß₃ and _vß₅ integrins in angiogenesis and the use of integrin antagonists as effective antiangiogenic agents are documented. Radiotherapy is an important therapy option for cancer. It has been shown that ionizing radiation exerts primarily antiangiogenic effects in tumors but has also proangiogenic effects as the reaction of the tumor to protect its own vasculature from radiation damage. Here, we show that combined treatment with S247, an Arg-Gly-Glu peptidomimetic antagonist of _vß₃ integrin, and external beam radiotherapy are beneficial in local tumor therapy. We found that radiation up-regulates _vß₃ expression in endothelial cells and consecutively phosphorylates Akt, which may provide a tumor escape mechanism from radiation injury mediated by integrin survival signaling. In the presence of S247, the radiation-induced Akt phosphorylation is strongly inhibited. Our studies on endothelial cell proliferation, migration, tube formation, apoptosis, and clonogenic survival show that the radiosensitivity of endothelial cells is enhanced by the concurrent administration of the integrin antagonist. The in vitro data are successfully translated into human glioma (U87), epidermoid (A431), and prostate cancer (PC3) xenograft models growing s.c. on BALB/c-nu/nu mice. In vivo, the combination of S247 treatment and fractionated radiotherapy (5 x 2.5 Gy) leads to enhanced antiangiogenic and antitumor effects compared with either monotherapies. These results underline the importance of _vß₃ integrin when tumors protect their microvasculature from radiation-induced damage. The data also indicate that the combination of integrin antagonists and radiotherapy represents a rational approach in local cancer therapy.

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