| Summary: | In this study, we test the hypothesis that an in vivo DNA double-strand break (DSB) repair assay performed in irradiated human skin correlates with severity of late toxicities following breast radiotherapy, as opposed to the same assay performed in ex vivo irradiated blood lymphocytes. Applying a comparative analysis approach, levels of residual DSB were judged to be significantly higher among patients who presented with late adverse effects in their breasts (cases) than controls who had minimal/no effects, but this was only observed in blood lymphocytes. In conjunction with this observation, although DSB repair was comparable between different skin cells, residual DSB levels were not correlated between skin cells and blood lymphocytes of the same patients. These findings suggest that cellular DSB repair may be influenced by factors relating to the tissue microenvironment, and support the notion that blood lymphocytes represent a valid cellular system for testing of predictive markers of normal tissue radiosensitivity. Next, chromosomal radiosensitivity and radiation-induced apoptosis were tested as markers of clinical radiosensitivity among a subset of severe cases and matched controls. Unlike levels of apoptosis in irradiated blood lymphocytes which were comparable between both groups of patients, levels of chromosomal aberrations were significantly higher in irradiated blood lymphocyte metaphases of severe cases, suggesting that likewise to DSB repair, chromosomal radiosensitivity could be a potential marker of clinical radiosensitivity. Crude tests of association were performed to determine if different cellular radiation responses were correlated within the same individuals. Levels of residual DSB were closely related to the formation of excess acentric fragments in the same patients, while separately, induction of apoptosis was found to be independent of DSB repair. Interactions between DSB repair and apoptosis induction were further examined and a mechanistic model linking these radiation responses is proposed.
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