Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency

We investigated whether cilengitide could amplify the antitumor effects of radiotherapy in an orthotopic rat glioma xenograft model. Cilengitide is a specific inhibitor of alpha v series integrins, and acts as an antiangiogenic. U251 human glioma cells express alpha v beta 3 and alpha v beta 5 integrins. We used in vitro assays of adhesion and growth of tumor and endothelial cells to evaluate cytotoxicity an the potential for cilengitide to enhance radiation toxicity. Treatment was then evaluated in an orthotopic model to evaluate synergy with therapeutic radiation in vivo. In vitro, cilengitide blocked cell adhesion, but did not influence the effects of radiation on U251 cells; cilengitide strongly amplified radiation effects on endothelial cell survival. lit vivo, radiotherapy prolonged the survival of U251 tumor-bearing rats from 50 to over 110 as. Cotreatment with cilengitide and radiation dramatically amplified the effects of radiation, producing survival over 200 days and triggering an enhanced apoptotic response and suppression of to or growth by histology at necropsy. Signaling pathways activated in the tumor included NF kappa b, a documented mediator of cellular response to radiation. Because cilengitide has a short plasma half-life (t(1/2) similar to 20 min), antiangiogenic scheduling typically uses daily injections. We found that a single dose of cilengitide (4 mg/kg) given between 4 and 12 hr prior to radiation was sufficient to produce the same effect. Our results demonstrate that blockade of alpha v integrins mediates an unanticipated rapid potentiation of radiation, and suggests possible clinical translation for glioma therapy. (C) 2008 Wiley-Liss, Inc.