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An Integrated theoretical model for estimating cell death based on the DNA damage response

Matsuya, Yusuke ; McMahon, S. J.*; Sato, Tatsuhiko  ; Butterworth, K. T.*; Saga, Ryo*; Date, Hiroyuki*; Prise, K. M.*

Ionizing radiation has the potential to induce damage to DNA and subsequent late biological effects such as cell death. Amongst the types of DNA lesions, DNA double-strand breaks (DSBs) have been known as the principal damage form leading to cell death with a certain probability. To date, early DSB induction and the repair dynamics have been experimentally investigated, yet the optimum approach to directly evaluate the relationship between DSBs and cell death remain unclear. To solve this problem, we have developed a theoretical cell-killing model, the integrated microdosimetric-kinetic (IMK) model, which considers the responses of sub-lethal damage (corresponding to DSB) after irradiation and several biological factors, such as cell-cycle phase, oxygen pressure and intercellular communication. Using the IMK model, we have successfully reproduced experimental DSBs and survival data for various irradiation conditions and cell conditions. In this study, we introduce an overview of the IMK model. In particular, focusing on early DSBs yield and the repair kinetics, we present the latest estimation results for interpreting the cellular mechanisms of intercellular communication and oxygen effects. In the future, by developing an integrated package enabling to estimate cellular responses in the combination of the PHITS code and the IMK model, it will be expected to clarify the relationship between initial DNA damage and late biological effects, such as cell death and mutation.

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