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Tissue overreactions (OR), whether called adverse effects, radiotoxicity, or radiosensitivity reactions, may occur during or after anti-cancer radiotherapy (RT). They represent a medical, economic, and societal issue and raise the question of individual response to radiation. To predict and prevent them are among the major tasks of radiobiologists. To this aim, radiobiologists have developed a number of predictive assays involving different cellular models and endpoints. To date, while no consensus has been reached to consider one assay as the best predictor of the OR occurrence and severity, radiation oncologists have proposed consensual scales to quantify OR in six different grades of severity, whatever the organ/tissue concerned and their early/late features. This is notably the case with the Common Terminology Criteria for Adverse Events (CTCAE). Few radiobiological studies have used the CTCAE scale as a clinical endpoint to evaluate the statistical robustness of the molecular and cellular predictive assays in the largest range of human radiosensitivity. Here, by using 200 untransformed skin fibroblast cell lines derived from RT-treated cancer patients eliciting OR in the six CTCAE grades range, correlations between CTCAE grades and the major molecular and cellular endpoints proposed to predict OR (namely, cell survival at 2 Gy (SF2), yields of micronuclei, recognized and unrepaired DSBs assessed by immunofluorescence with γH2AX and pATM markers) were examined. To our knowledge, this was the first time that the major radiosensitivity endpoints were compared together with the same cohort and irradiation conditions. Both SF2 and the maximal number of pATM foci reached after 2 Gy appear to be the best predictors of the OR, whatever the CTCAE grades range. All these major radiosensitivity endpoints are mathematically linked in a single mechanistic model of individual response to radiation in which the ATM kinase plays a major role.

The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term "radiosensitivity" was used by the pioneers at the beginning of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell death, a confusion emerged in the literature from the 1930s, as "radiosensitivity" was indifferently used to describe the toxic, cancerous, or aging effect of IR. In parallel, the predisposition to radiation-induced adverse tissue reactions (radiosensitivity), notably observed after radiotherapy appears to be caused by different mechanisms than those linked to predisposition to radiation-induced cancer (radiosusceptibility). This review aims to document these differences in order to better estimate the different radiation-induced risks. It reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair as their role is absolutely necessary for cell viability. By contrast, some cytoplasmic proteins whose functions are independent of genome surveillance may also act as phosphorylation substrates of the ATM protein to regulate the molecular response to IR. The role of the ATM protein may help classify the genetic syndromes associated with radiosensitivity and/or radiosusceptibility.

Radiation-induced bystander effects (RIBE) describe the biological events occurring in non-targeted cells in the vicinity of irradiated ones. Various experimental procedures have been used to investigate RIBE. Interestingly, most micro-irradiation experiments have been performed with alpha particles, whereas most medium transfers have been done with X-rays. With their high fluence, synchrotron X-rays represent a real opportunity to study RIBE by applying these two approaches with the same radiation type. The RIBE induced in human fibroblasts by the medium transfer approach resulted in a generation of DNA double-strand breaks (DSB) occurring from 10 min to 4 h post-irradiation. Such RIBE was found to be dependent on dose and on the number of donor cells. The RIBE induced with the micro-irradiation approach produced DSB with the same temporal occurrence. Culture media containing high concentrations of phosphates were found to inhibit RIBE, while media rich in calcium increased it. The contribution of the RIBE to the biological dose was evaluated after synchrotron X-rays, media transfer, micro-irradiation, and 6 MeV photon irradiation mimicking a standard radiotherapy session: the RIBE may represent less than 1%, about 5%, and about 20% of the initial dose, respectively. However, RIBE may result in beneficial or otherwise deleterious effects in surrounding tissues according to their radiosensitivity status and their capacity to release Ca2+ ions in response to radiation. [ABSTRACT FROM AUTHOR]