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Journal Articles

Tumor radioresistance caused by radiation-induced changes of stem-like cell content and sub-lethal damage repair capability

Fukui, Roman*; Saga, Ryo*; Matsuya, Yusuke; Tomita, Kazuo*; Kuwahara, Yoshikazu*; Ouchi, Kentaro*; Sato, Tomoaki*; Okumura, Kazuhiko*; Date, Hiroyuki*; Fukumoto, Manabu*; et al.

Scientific Reports (Internet), 12(1), p.1056_1 - 1056_12, 2022/01

Alive cancer cells after fractionated irradiations with 2 Gy X-rays per day for more than 30 days show clinically relevant radioresistant. Such radioresistance is experimentally interpreted to attributed to the increment of stem-like cell content. However, only an experimental approach cannot clarify the cell responses (DNA damage and cell death induction) of cancer stem cells, so the radioresistant mechanisms remain uncertain. In addition to the conventional cell experiments using radio-resistant cell lines established after fractionated irradiations, in this study we developed a mathematical model (so called integrated microdosimetric-kinetic (IMK) model) explicitly considering cancer stem-like cell content and DNA damage responses and investigated radioresistant mechanisms acquired after fractionated irradiations. The IMK model analysis suggested that the changes of stem-like cell fraction and DNA repair efficiency play important roles of radioresisitance acquired after irradiations. Considering these into the IMK model, we successfully reproduced the experimental survival of various cell lines and various irradiation conditions. This work would contribute to not only the precise understanding of the radioresistant mechanisms induced after irradiation but also predicting curative effects with high precision.

Journal Articles

Oxygen enhancement ratios of cancer cells after exposure to intensity modulated X-ray fields; DNA damage and cell survival

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:0 Percentile:0.01(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.

Journal Articles

4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication

Saga, Ryo*; Matsuya, Yusuke; Takahashi, Rei*; Hasegawa, Kazuki*; Date, Hiroyuki*; Hosokawa, Yoichiro*

Scientific Reports (Internet), 11(1), p.8258_1 - 8258_10, 2021/04

 Times Cited Count:0 Percentile:0(Multidisciplinary Sciences)

Hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which indicates the involvement of intercellular communication. In addition, the oxidative stress level, which leads to DNA damage induction, significantly increased under 4-MU treatment, and the radiosensitization by 4-MU can be suppressed by the inhibitors for intercellular communication. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.

Journal Articles

Comparative study on performance of various environmental radiation monitors

Tamakuma, Yuki*; Yamada, Ryohei; Suzuki, Takahito*; Kuroki, Tomohiro*; Saga, Rikiya*; Mizuno, Hiroyuki*; Sasaki, Hiroyuki*; Iwaoka, Kazuki*; Hosoda, Masahiro*; Tokonami, Shinji*

Radiation Protection Dosimetry, 184(3-4), p.307 - 310, 2019/10

 Times Cited Count:1 Percentile:23.13(Environmental Sciences)

After the Fukushima Daiichi Nuclear Power Plant accident, the radiation dose for first responders was not evaluated accurately due to lack of the monitoring data. It has been important to evaluate a radiation dose for workers in emergency response at a nuclear accident. In this study, a new device which can evaluate both of external and internal exposure doses was developed and the performance of various environmental radiation monitors including commercially available monitors were tested and compared from the viewpoint of an environmental monitoring at emergency situation. Background counts of the monitors and the ambient dose equivalent rate were measured in Fukushima Prefecture. The detection limit for beta particles was evaluated by the method of ISO11929. The sensitivity for gamma-rays of the dust monitor using a ZnS(Ag) and a plastic scintillator was high, but that of the external exposure monitor using a silicon photodiode with CsI(Tl) crystal was relatively low. The detection limit ranged 190-280 Bq m$$^{-3}$$ at 100 $$mu$$Sv h$$^{-1}$$, exceeding the detection limit of 100 Bq m$$^{-3}$$ in the minimum requirement by the National Regulation Authority in Japan. Use of the shielding with lead is necessary to achieve the minimum requirement. These results indicate that the dust monitor using a ZnS(Ag) scintillator and a plastic scintillator is suitable for the external exposure monitor and the developed internal exposure monitor is for the internal exposure monitor at emergency situation among the evaluated monitors. In the future study, the counting efficiency, the relative uncertainty and the performance of the detection for alpha particles will be evaluated, and it will be considered which type of a monitor is suitable after taking the portability into account.

Journal Articles

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

Saga, Ryo*; Matsuya, Yusuke; Takahashi, Rei*; Hasegawa, Kazuki*; Date, Hiroyuki*; Hosokawa, Yoichiro*

Journal of Radiation Research, 60(3), p.298 - 307, 2019/05

 Times Cited Count:13 Percentile:87.98(Biology)

In radiotherapy, it is recognized that cancer stem cells (CSCs) in tumor tissue shows radio-resistance. However, the relationship between content percentage of the CSCs and dose-response curve on cell survival remain unclear. In this study, we developed a stochastic model considering progeny cells and stem cells, and investigated the impact of stem cells on radio-sensitivity. From the flow-cytometric analysis (cell experiments), the content percentage of stem cells was 3.2% or less which agreed well with the model estimation from the cell survival curve. Based on the verification, it is suggested that cell survival in high-dose range is largely affected by the CSCs. In addition, regarding the sub-population of stem cells, the present model well reproduces the dose response on lethal lesions to DNA comparing with the conventional LQ model. This outcome indicates that the stem cells must be considered for describing the dose-response curve in wide dose range.

Journal Articles

Effects of ion-beam irradiation on germination and growth of seedlings of red pepper "Hirosaki zairai"

Tomikawa, Masaru*; Maeda, Tomoo*; Honda, Kazushige*; Saga, Koichi*; Ishikawa, Ryuji*; Akita, Yusuke; Yoshihara, Ryohei; Nozawa, Shigeki; Narumi, Issei

JAEA-Review 2010-065, JAEA Takasaki Annual Report 2009, P. 73, 2011/01

Oral presentation

Effect of ion beam irradiation to seeds on generation and growth in the seedling of capsicum native variety in Hirosaki

Maeda, Tomoo*; Tomikawa, Masaru*; Honda, Kazushige*; Saga, Koichi*; Ishikawa, Ryuji*; Akita, Yusuke; Yoshihara, Ryohei; Nozawa, Shigeki; Narumi, Issei

no journal, , 

no abstracts in English

Oral presentation

Expression of mutations in the M2 generation of red pepper "Hirosaki zairai" irradiated with ion beam

Sato, Yusuke*; Maeda, Tomoo*; Honda, Kazushige*; Saga, Koichi*; Ishikawa, Ryuji*; Akita, Yusuke; Yoshihara, Ryohei; Nozawa, Shigeki; Narumi, Issei

no journal, , 

no abstracts in English

Oral presentation

Investigation of radiosensitivity enhanced by inflammatory responses after irradiation based on a cell-killing model considering non-targeted effects

Takahashi, Rei*; Saga, Ryo*; Matsuya, Yusuke; Hasegawa, Kazuki*; Fukui, Roman*; Hosokawa, Yoichiro*

no journal, , 

Inflammatory responses after irradiation induce antioxidant activity, leading to radioresistance in cancer cells. In our previous study, it was found that a hyaluronan synthesis inhibitor (4-MU) can suppress inflammatory responses, however the underlying mechanisms are still unknown. In this study, we aimed to clarify the radiosensitization mechanism induced by 4-MU in the application of cell-killing models. In terms of in vitro experiments, cultured human fibrosarcoma cells were exposed to X-rays in presence of 100 $$mu$$M 4-MU and scavenger of intercellular signalling (1% DMSO, 40 $$mu$$M c-PTIO), and we measured the relation between dose and cell viability by means of colony assay. The experimental results were also interpreted by using integrated cell-killing model which has been developed so as to consider non-targeted effects. From the experiments, it was found that a combination of 4-MU treatment and irradiation significantly reduced the cell survival. This reduced viability was suppressed in the presence of DMSO or c-TPIO. Meanwhile, the model analysis showed such an increase of cell-killing is predominantly attributed by non-targeted effects. These results suggest that the radiosensetization promoted by 4-MU treatment is predominantly attributed to the accumulation in non-targeted effects.

Oral presentation

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.*

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.

Oral presentation

Investigation of radioresistant mechanisms in oral squamous cell carcinoma cells in in hypoxic environment

Tosa, Nanami*; Saga, Ryo*; Matsuya, Yusuke; Hosokawa, Yoichiro*

no journal, , 

Cancer cells exposed to a hypoxic environment show malignant progression such resistant to both chemotherapy and radiotherapy. During fractionated radiotherapy (e.g., 2 Gy/fraction), due to broken fragile blood vessels, cancer cells near blood vessels are exposed to a hypoxic environment, leading to cancer stem-like cells (CSCs) niches and reduced radiosensitivity. However, the radioresistant mechanisms of cancer cells in hypoxia remain uncertain. In this study, we investigated the relationship between CSC fraction and radioresistance in hypoxia. The experimental results on surviving fraction of oral squamous cell carcinoma cells (HSC3 cells) shows that the radiosensitivity can be reduced as exposure time of hypoxia becomes longer. Meanwhile, using the integrated cell-killing model explicitly considering oxygen effects and CSC population (so called integrated microdosimetric-kinetic (IMK) model), the reduced radiosensitivity could be reproduced by reduced DNA damage yield and increased CSC fraction due to lack of oxygen. This work would contribute to the radioresistant mechanisms and the precise understanding of the therapeutic effects during fractionated radiotherapy.

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