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Antiangiogenic Therapy with Mammalian Target of Rapamycin Inhibitor RAD001 (Everolimus) Increases Radiosensitivity in Solid Cancer

Authors' Affiliations: Departments of ¹ Surgery and ² Radiation Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany

Requests for reprints: Philipp Manegold, Department of Surgery, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. Phone: 49-89-7095-3430; Fax: 49-89-7095-6433; E-mail: Philipp.Manegold{at}med.uni-muenchen.de.

Purpose: Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth.

Experimental Design: Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 x 2 or 5 x 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy.

Results: A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (–16%), CT-26 (–70%), and human umbilical vascular endothelial cells (HUVEC; –72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (–83%), L3.6pl (–8%), and CT-26 (–82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (–57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 x 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm³ versus 1144 mm³; CT-26: 210 mm³ versus 636 mm³; P < 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy.

Conclusion: Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.