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Inactivation of gadd45a Sensitizes Epithelial Cancer Cells to Ionizing Radiation In vivo Resulting in Prolonged Survival

¹ Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ² Division of Basic Science, National Cancer Institute, NIH, Bethesda, Maryland; and ³ Lombardi Cancer Center, Georgetown University, Washington, District of Columbia

Requests for reprints: Terry Van Dyke, Lineberger Cancer Center, University of North Carolina at Chapel Hill, CB7295, 100 West Drive, Chapel Hill, NC27599-7295. Phone: 919-962-2145; Fax: 919-843-3160; E-mail: tvdlab{at}med.unc.edu.

Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in IR-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management. [Cancer Res 2008;68(10):3579–83]