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Matsuya, Yusuke; McMahon, S. J.*; Butterworth, K. T.*; Yachi, Yoshie*; Saga, Ryo*; Sato, Tatsuhiko; Prise, K. M.*
Physics in Medicine & Biology, 68(9), p.095008_1 - 095008_12, 2023/04
Times Cited Count：1 Percentile：65.01(Engineering, Biomedical)Hypoxia induces radioresistance in tumors, leading to malignant progression in intensity-modulated radiation therapy. To date, it has been shown that intercellular signalling between cells positioned inside and outside radiation field impacts on cellular radiosensitivity under hypoxia and normoxia. However, the mechanistic role of intercellular communication in hypoxia remains to be fully understood. In this study, we modelled the cell-killing effects of intercellular signalling in hypoxia to better understand the underlying mechanisms of response. We used the oxygen enhancement ratio (OER) given from early DSB yields and modelled the in- and out-of-field radiosensitivity. As a result, the model analysis provides an mechanistical interpretation that the probability of hits for releasing cell-killing signals is dependent on oxygen. Our data also suggested that the field-type independent OER value, which can be given by uniform-field exposure, can be applied when predicting both in- and out-of-field radiosensitivity. These results would contribute to more precise understanding of intercellular signalling under heterogeneous exposure to intensity-modulated radiation fields.
Matsuya, Yusuke; McMahon, S. J.*; Butterworth, K. T.*; Naijo, Shingo*; Nara, Isshi*; Yachi, Yoshie*; Saga, Ryo*; Ishikawa, Masayori*; Sato, Tatsuhiko; Date, Hiroyuki*; et al.
Physics in Medicine & Biology, 66(7), p.075014_1 - 075014_11, 2021/04
Times Cited Count：4 Percentile：47.6(Engineering, Biomedical)Hypoxic cancer cells within solid tumours show radio-resistance, leading to malignant progression in fractionated radiotherapy. When prescribing dose to tumours under heterogeneous oxygen pressure with intensity-modulated radiation fields, intercellular signalling could have an impact on radiosensitivity between in-field and out-of-field cells. However, the impact of hypoxia on radio-sensitivity under modulated radiation intensity remains uncertain. In this study, we investigate the impact of hypoxia on in-field and out-of-field radio-sensitivities using two types of cancer cells. These in vitro measurements indicate that hypoxia apparently impacts out-of-field cells, although the OER values in out-of-field cells were smaller compared to those for in-field and uniformly irradiated cells. These decreased radio-sensitivities of out-of-field cells were shown as a consistent tendency for both DSB and cell death endpoints, suggesting that radiation-induced intercellular communication is of importance in treatment planning with intensity-modulated radiotherapy.
Matsuya, Yusuke; McMahon, S. J.*; Sato, Tatsuhiko; Butterworth, K. T.*; Saga, Ryo*; Date, Hiroyuki*; Prise, K. M.*
no journal, ,
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.
