Abstract 67: A Novel Survivin-Mediated Adaptive Response Induced by Very Low Dose Imaging-Level Exposures and Radiation Therapy.

Abstract Exposure of cells to a very low dose of ionizing radiation can induce an enhanced resistance or adaptive response to a subsequent larger radiation dose as evidenced by an increase in cell survival. This expression of an adaptive response has been attributed to the result of signaling processes induced by very low radiation doses in the range of 0.5 to 100 mGy. The radiation-induced adaptive response is garnering considerable attention now due in part to the burgeoning increase in the use of imaging technologies such as computerized axial tomography and portal imaging to monitor tumor response and positioning during multi-dose standard radiation therapy protocols. The focus of this study was to investigate whether this process could occur when the delivery of the very small radiation dose was administered before or in between the administration of two typically used radiation therapy level doses. Specifically, could this signaling process be perturbed by the addition of a second 2 Gy dose of ionizing radiation delivered at a relatively short time interval from the exposure of cells to the very low dose? A human colon carcinoma cell line (RKO36) along with transformed mouse embryo fibroblasts (MEF), both wild type (WT) or tumor necrosis factor receptor 1 and 2 knockout cells (TNFR1−2−) were grown to confluence in vitro or as MEF tumors in the flank of C57BL/6 mice. Changes in SOD2 enzymatic activity, survivin protein, apoptosis, and cell survival as a function of radiation conditions and transfection of cells with SOD2-or survivin siRNA were determined. An adaptive response was induced in cells at all doses tested from 5 to 100 mGy. The adaptive responses measured in all three cell lines were associated with a reduction in apoptosis frequencies, a 5 to 20% increase in cell survival, and a rapid 2 to 3 fold elevation in survivin protein levels. Very low dose radiation-induced elevation in survivin levels was completely inhibited by transfection of cells with survivin siRNA. This was accompanied by an increase in apoptosis and a loss of the expression of these survival related adaptive responses. We have identified a very low radiation dose-induced survivin-mediated adaptive response that may affect therapeutic outcomes associated with increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.) Citation Format: Jeffrey S. Murley, Richard C. Miller, Helena J. Mauceri, Harold G. Sutton, Ralph R. Weichselbaum, David J. Grdina. A novel survivin-mediated adaptive response induced by very low dose imaging-level exposures and radiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 67. doi:10.1158/1538-7445.AM2013-67