Investigation of dose-rate effects and cell-cycle distribution under protracted exposure to ionizing radiation for various dose-rates

Matsuya, Yusuke; McMahon, S. J.; Tsutsumi, Kaori; Sasaki, Kohei; Okuyama, Go; Yoshii, Yukie; Mori, Rintaro; Oikawa, Joma; Prise, Kevin M.; Date, Hiroyuki

doi:10.1038/s41598-018-26556-5

Cited by 51 publications

(126 citation statements)

References 54 publications

(109 reference statements)

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“…To investigate the contribution of CSCs to the dose–response curve, we developed a cell-killing model composed of two cell populations based on the integrated microdosimetric-kinetic (IMK) model for acute irradiation [13, 15, 22]. The IMK model enables us to evaluate the impact of intercellular communication as well as microdosimetry on the dose–response curve, so we selected the IMK model not the LQ model for developing the integrated modeling.…”

Section: Methodsmentioning

confidence: 99%

“…The linear–quadratic (LQ) model, which quantitatively describes the relationship between absorbed dose and fraction of cells surviving, is widely used for determining the treatment planning in multifractionated radiotherapy [12]. Although the LQ model is preferred for reasons of simplicity and consistency with cell experiments and clinical outcomes, the model does not explicitly include radiosensitive factors, such as dose-rate effects and cell-cycle dependency [13–15]. Several cell-killing models considering radiosensitive factors (such as microdosimetry, dose-rate effects and intercellular communication) have been proposed for providing the relationship between absorbed dose and cell survival [16–22].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of the high-dose-range radioresistance of prostate cancer cells, including cancer stem cells, based on a stochastic model

Saga

Matsuya

Takahashi

et al. 2019

Journal of Radiation Research

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In radiotherapy, cancer stem cells (CSCs) are well recognized as one of the radioresistant cell types. Even in a small subpopulation, CSCs may have an influence on tumor control probability, represented by cell killing after irradiation. However, the relationship between the percentage content of CSCs and the cell survival dose–response curve has not yet been quantitatively clarified. In this study, we developed a cell-killing model for two cell populations (CSCs and progeny cells) to predict the surviving fractions, and compared it with the conventional linear–quadratic (LQ) model. Three prostate cancer cell lines (DU145, PC3 and LNCaP) were exposed to X-rays at doses ranging from 0 to 10 Gy. After the irradiation, we performed clonogenic survival assays to generate the cell survival curves, and carried out flow-cytometric analyses to estimate the percentage content of CSCs for each cell line. The cell survival curves for DU145 cells and PC3 cells seemed not to follow the conventional LQ model in the high dose range (>8 Gy). However, the outputs of the developed model agreed better with the experimental cell survival curves than those of the LQ model. The percentage content of CSCs predicted by the developed model was almost coincident with the measured percentage content for both DU145 cells and PC3 cells. The experiments and model analyses indicate that a small subpopulation of radioresistant CSCs has lower radiosensitivity in the high-dose range, which may lessen the clinical outcome for patients with prostate cancer after high-dose radiation therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of the high-dose-range radioresistance of prostate cancer cells, including cancer stem cells, based on a stochastic model

Saga

Matsuya

Takahashi

et al. 2019

Journal of Radiation Research

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“…11 The inverse dose-rate effect can be observed at dose-rates below 1 Gy/h in cells showing LDHRS. 11,12 The LDHRS and the inverse dose-rate effect were exploited in pulsed low-dose rate (PLDR) radiotherapy as a treatment strategy combining multiple low doses (hyperfractionation) in a pulsed delivery to reduce the effective dose-rate. 13 Its effectiveness was evaluated first in the radioresistant gliomas.…”

Section: Introductionmentioning

confidence: 99%

Pulsed low dose-rate irradiation response in isogenic HNSCC cell lines with different radiosensitivity

Todorović

Prevc

Žakelj

et al. 2020

Radiology and Oncology

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BackgroundManagement of locoregionally recurrent head and neck squamous cell carcinomas (HNSCC) is challenging due to potential radioresistance. Pulsed low-dose rate (PLDR) irradiation exploits phenomena of increased radiosensitivity, low-dose hyperradiosensitivity (LDHRS), and inverse dose-rate effect. The purpose of this study was to evaluate LDHRS and the effect of PLDR irradiation in isogenic HNSCC cells with different radiosensitivity.Materials and methodsCell survival after different irradiation regimens in isogenic parental FaDu and radioresistant FaDu-RR cells was determined by clonogenic assay; post irradiation cell cycle distribution was studied by flow cytometry; the expression of DNA damage signalling genes was assesed by reverse transcription-quantitative PCR.ResultsRadioresistant Fadu-RR cells displayed LDHRS and were more sensitive to PLDR irradiation than parental FaDu cells. In both cell lines, cell cycle was arrested in G2/M phase 5 hours after irradiation. It was restored 24 hours after irradiation in parental, but not in the radioresistant cells, which were arrested in G1-phase. DNA damage signalling genes were under-expressed in radioresistant compared to parental cells. Irradiation increased DNA damage signalling gene expression in radioresistant cells, while in parental cells only few genes were under-expressed.ConclusionsWe demonstrated LDHRS in isogenic radioresistant cells, but not in the parental cells. Survival of LDHRS-positive radioresistant cells after PLDR was significantly reduced. This reduction in cell survival is associated with variations in DNA damage signalling gene expression observed in response to PLDR most likely through different regulation of cell cycle checkpoints.

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“…For example, the time factor in the microdosimetric-kinetic (MK) model 28 represents the sub-lethal damage repair (SLDR) rate which can be deduced from a split-dose cell recovery curve 30 . Amongst many models developed by several researchers 15,28–33 , the “ integrated microdosimetric-kinetic ( IMK ) model ” 34,35 is suitable for analysing impact of IC for intensity-modulated fields and SLDR during irradiation. From in vitro experiments for modulated fields, we have also used this modelling approach to interpret the mechanisms of the radio-resistance.…”

Section: Introductionmentioning

confidence: 99%

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects

Matsuya¹,

McMahon²,

Ghita³

et al. 2019

Sci Rep

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In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area of a T25 flask containing the cells (half-field) or 100% of the flask (uniform-field). We also modelled the impact of dose-rate effects and intercellular signalling on cell-killing. Applying the model to the survival data, it is found that (i) in-field cell survival under half-field exposure is higher than uniform-field exposure for the same delivered dose; (ii) the importance of sub-lethal damage repair (SLDR) in AGO1522 cells is reduced under half-field exposure; (iii) the yield of initial DNA lesions measured with half-field exposure is smaller than that with uniform-field exposure. These results suggest that increased cell survival under half-field exposure is predominantly attributed not to rescue effects (increased SLDR) but protective effects (reduced induction of initial DNA lesions). In support of these protective effects, the reduced DNA damage leads to modulation of cell-cycle dynamics, i.e., less G 1 arrest 6 h after irradiation. These findings provide a new understanding of the impact of dose-rate effects and protective effects measured after modulated field irradiation.

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Investigation of dose-rate effects and cell-cycle distribution under protracted exposure to ionizing radiation for various dose-rates

Cited by 51 publications

References 54 publications

Analysis of the high-dose-range radioresistance of prostate cancer cells, including cancer stem cells, based on a stochastic model

Analysis of the high-dose-range radioresistance of prostate cancer cells, including cancer stem cells, based on a stochastic model

Pulsed low dose-rate irradiation response in isogenic HNSCC cell lines with different radiosensitivity

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects

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