The yield of DNA double strand breaks determined after exclusion of those forming from heat-labile lesions predicts tumor cell. radiosensitivity to killing

Background and purpose: The radiosensitivity to killing of tumor cells and in-field normal tissue are key determinants of radiotherapy response. In vitro radiosensitivity of tumor- and normal-tissue-derived cells often predicts radiation response, but high determination cost in time and resources compromise utility as routine response-predictor. Efforts to use induction or repair of DNA double-strand-breaks (DSBs) as surrogate-predictors of cell radiosensitivity to killing have met with limited success. Here, we re-visit this issue encouraged by our recent observations that ionizing radiation (IR) induces not only promptly-forming DSBs (prDSBs), but also DSBs developing after irradiation from the conversion to breaks of thermally-labile sugar-lesions (tlDSBs). Materials and methods: We employ pulsed-field gel-electrophoresis and flow-cytometry protocols to. measure total DSBs (tDSB = prDSB + tlDSBs) and prDSBs, as well as gamma H2AX and parameters of chromatin structure. Results: We report a fully unexpected and in many ways unprecedented correlation between yield of prDSBs and radiosensitivity to killing in a battery of ten tumor cell lines that is not matched by yields of tDSBs or gamma H2AX, and cannot be explained by simple parameters of chromatin structure. Conclusions: We propose the introductIon of prDSBs-yield as a novel and powerful surrogate-predictor of cell radiosensitivity to killing with potential for clinical application. (C) 2015 Elsevier Ireland Ltd. All rights reserved.