Abstract 861: Survivin-mediated adaptive response: a risk factor for IGRT

Abstract

Abstract Exposure of cells to very low doses of ionizing radiation can induce an enhanced resistance or adaptive response to a subsequent larger radiation dose as demonstrated by an increase in cell survival. Expression of a radio-adaptive response has been attributed to pro-survival signaling processes induced by very low radiation doses in the range of 5 to 100 mGy. The radiation-induced adaptive response is gaining considerable attention due in part to the expanding 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 very small imaging radiation dose was administered prior to or following the administration of the first of two typically used radiation therapy level doses. SA-NH mouse sarcoma cells and SA-NH cells stably transfected with mutated IκBα (SA-NH+mIκBα1) to inhibit the activation of NFκB were grown to confluence in vitro or as tumors in the right hind leg of C3H mice. Percentage of cell survival, apoptosis frequencies and survivin protein levels were determined as a function of radiation conditions and transfection of cells with survivin siRNA. A significant radio-adaptive response was observed in cells exposed to 5 mGy - 100 mGy 15 min to 6 h prior to or after irradiation with the first of two 2 Gy therapeutic radiation doses and was associated with a concomitant reduction in apoptosis frequencies and a rapid elevation in survivin protein levels. The very low dose radiation-induced elevation in survivin levels, the reduction in apoptosis frequencies and enhanced cell survival were not observed in SA-NH+mIκBα1 cells or SA-NH cells transfected with survivin siRNA. We have identified a very low radiation dose-induced survivin-mediated adaptive response that could compromise therapeutic outcomes associated with the 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: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Gayle E. Woloschak, Jian Jian Li, Ralph R. Weichselbaum. Survivin-mediated adaptive response: a risk factor for IGRT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2014-861