Abstract
Mechanistic approaches to modeling the effects of ionizing radiation on cells are on the rise, promising a better understanding of predictions and higher flexibility concerning conditions to be accounted for. In this work we modified and extended a previously published mechanistic model of cell survival after photon irradiation under hypoxia to account for radiosensitization caused by deficiency or inhibition of DNA damage repair enzymes. The model is shown to be capable of describing the survival data of cells with DNA damage repair deficiency, both under norm- and hypoxia. We find that our parameterization of radiosensitization is invariant under change of oxygen status, indicating that the relevant parameters for both mechanisms can be obtained independently and introduced freely to the model to predict their combined effect.
Highlights
Radiation therapy is one of the cornerstones of cancer care, where ~50% of patents receive radiation during the course of disease [1]
Radiobiological modeling is an integral part of radiation oncology and radiation therapy, used to predict normal and tumor tissue response, which is of particular significance when moving towards personalized radiation treatment, including treatment gap corrections, normal tissue tolerance predictions, optimization of therapy determined by predictive assays, multi-modality schedule design, and the simulation of clinical trials [2]
One of the key strategies to overcome the radioresistance in hypoxic cells is a dual treatment, i.e., a combined treatment with photon irradiation and administration of radiosensitizing drugs, such as DNA damage response (DDR) inhibitors [7,8,9,10]
Summary
Radiation therapy is one of the cornerstones of cancer care, where ~50% of patents receive radiation during the course of disease [1]. To further extend the model and describe the particular case of hypoxic tumor cells response to dual treatment, radiotherapy, and DDR inhibition, we introduced a so-called radiosensitization factor (RSF) that modifies KiDSB This is based on observations by Hufnagl et al [26], that the increased radiosensitivity of repair-deficient cell lines could be accounted for by increasing the lethality parameter of isolated DSB, while keeping the lethality parameter for complex DSB constant. Complex DSB are argued to pose such severe challenge to the DDR that any change in the repair capabilities of the cell has no effect on their lethality parameter To validate this extension, we benchmarked our model in two scenarios, using experimental data obtained from cells in which one of the two key radiation-induced DDR molecules, DNA-dependent protein kinase (DNA-PK) or ataxia-telangiectasia mutated (ATM), was impaired [29].
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