Low dose-rate fibroblast radiosensitivity and the prediction of patient response to radiotherapy

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Abstract
The relationship between cellular radiosensitivity and normal-tissue response to radiotherapy in individual cancer patients has attracted increasing attention over the last few years. Recent work has suggested that a correlation exists between fibroblast sensitivity and normal-tissue reactions. We have examined the radiosensitivity of fibroblasts grown from skin biopsies of four normal individuals and three patients identified as having suffered unexpectedly severe reactions to clinical radiotherapy, called here 'over-reactor' (OR) patients. Clonogenic survival was measured after high (HDR) and low dose-rate (LDR) irradiation. By comparing the two, and LDR Recovery Factor was derived. Potentially-lethal damage repair was examined in 4 cell strains. After HDR the OR strains were indistinguishable from the normals. At LDR the range of sensitivity was expanded. The OR strains fell at the sensitive end of the range and were characterized by a lack of LDR recovery, which clearly distinguished them from the normal strains. Experimental errors were estimated by considering all the data sets together rather than viewing each experiment individually. Duplicate strains from several patients were tested, and the differences between them were found to be within the estimated experimental errors, suggesting that these differences were not biologically significant. The data are consistent with the hypothesis that normal-tissue response is linked to individual cellular radiosensitivity. Our data confirm the importance of using LDR irradiation in clinical investigations of cellular sensitivity.