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Okayasu Ryuichi - One of the best experts on this subject based on the ideXlab platform.
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Strategies to Enhance Radiosensitivity to Heavy Ion RadiatIon Therapy
'International Journal of Particle Therapy', 2019Co-Authors: Lee Younghyun, Okayasu RyuichiAbstract:Heavy Ion radiatIon therapy has been increasingly used due to several advantages over low linear energy transfer (LET) photon therapy, but further improvement of its therapeutic efficacy would be necessary. In this review, we summarize effective radiosensitizers for Heavy Ion radiatIon therapy and mechanisms associated with the radiosensitizatIon. High LET Heavy Ions induce more complex and clustered DNA damage than low LET radiatIon. InhibitIon of homologous recombimatIon repair or nonhomologous end rejoining and dysfunctIonal cell cycle checkpoint have been reported to sensitize cancer cells to Heavy Ions. Radiosenstizing agents, including DNA damage response inhibitors, Hsp90 inhibitors, histone acetylase inhibitors, and nanomaterials have been found to enhance cell killing by Heavy Ion irradiatIon through disrupted DNA damage response, cell cycle arrest, or other cellular processes. The use of these radiosensitizers could be a promising strategy to enhance the efficacy of Heavy Ion radiatIon therapy
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High LET radiatIon uncovers a new aspect of DNA double strand break repair
2019Co-Authors: Okayasu Ryuichi, Okada Maki, Okabe Atsushi, Noguchi Miho, Takahashi SentaroAbstract:High LET Heavy Ion radiatIon has been successfully used for radiatIon cancer therapy and the biological effect is known to be more significant than low LET radiatIon such as X-rays. Despite its biological significance, the mechanism behind the high LET effect is not fully understood. In this presentatIon, the reason for the severe biological effects with high LET radiatIon is discussed in the context of DNA double strand break (DSB) repair, specifically non homologous end joining DSB repair pathway.We found LET dependent chromosome rejoining kinetics in normal human cells irradiated with 70 keV/um carbon and 200 keV/um iron Ions. Furthermore, the iron Ions seem to induce non-repairable DSB/chromosome damage. Using DSB repair deficient 180BR cells (DNA ligase IV mutant), a slow chromosome repair component (after 6h post-irradiatIon) was uncovered by comparing the iron and carbon rejoining kinetics. The experiment with phosphospecific antibody for DNA-PKcs also showed a significant delay in the phosphorylatIon process of this protein in cells exposed to high LET radiatIon when compared to X-rays. These results indicate that high LET Heavy Ion radiatIon induces DNA damage which is much more difficult to be repaired. The usefulness of high LET radiatIon to uncover the new mechanistic aspect of DNA DSB repair is also evident.日本放射線影響学会48回大会及び第1回アジア放射線研究会
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DNA double strand break repair under high and low LET radiatIon
2019Co-Authors: Okayasu Ryuichi, Okada Maki, Kato Takamitsu, Sekine Emiko, Okabe AtsushiAbstract:High LET Heavy Ion radiatIon has been successfully used for an alternative radiatIon treatment for cancer and is also an important component for space radiatIon. The biological effectiveness of high LET radiatIon (up to 200keV/um) is, in general, higher than that of low LET radiatIon such as X-rays and r-rays. One of the main causes of this is thought to be the difference in the way how cells process DNA damage, particularly DNA double strand breaks (DSBs). We have recently shown that the repair of DSBs depends on LET values, and DSB repair deficient cells show less dependency on LETs for their cell survival as well as DSB repair process. The inefficient repair of DSB associated with high LET radiatIon was also confirmed by a sensitive method, rH2AX assay. This inefficiency seems to result in misrejoining of chromosomes, leading to further severe biological consequences such as cell death and mutatIon. The misrepair/misrejoining could be shown by fluorescence in situ hybridizatIon (FISH) of chromosomes in irradiated cells. \nThe phosphorylatIon and de-phosphorylatIon of DNA-PKcs, a key protein for non-homologous end joining (NHEJ), was significantly delayed by irradiatIon of high LET carbon and iron Ions when compared to X-rays. Of interest, this phenomenon was further accentuated in the human NHEJ defective 180BR cells (shown below, Ref.: Radiat. Res. 165: 59-67 (2006))第7回 放射線生物学に関する日仏ワークショッ
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Comparison of initial chromosome break repair in cells irradiated with high and low LET radiatIon (+7 other presentatIons)
2019Co-Authors: Sekine Emiko, Okada Maki, Noguchi Miho, Yu Dong, Fujimori Akira, Okayasu RyuichiAbstract:The aim of this research is to determine the earliest biological effects at the chromosome level by high LET Heavy Ion radiatIon compared to those by X-rays in normal human cells (HFL III). We measured the number of chromosome breaks by the fusIon-induced premature chromosome condensatIon (PCC) assay. This assay is a cytogenetic method which can visualize chromosomes in inter-phase cells. As radiatIon sources, we used x-rays, carbon Ions (70 keV/um), neon Ions (70 keV/um, 200 keV/um), silicon Ions (70 keV/um, 200 keV/um), and iron Ions (200 keV/um). For all the PCC experiments, plateau cells (G0/G1 phase) were irradiated at 2Gy. In the process of fusIon-based PCC inductIon, cells have to be incubated at 37C, and the repair of DSBs can occur during this period. In order to detect chromosome breaks induced by irradiatIon at the earliest time point, we applied wortmannin (WM) to inhibit most of the DNA-PK dependent NHEJ type DSB repair during the incubatIon.In the case of X-rays about one half of the initial chromosome breaks were repaired, while almost no rejoining of initial breaks was observed in cells irradiated with silicon and iron particles. A correlatIon can be observed between the initial repair and the actual energy of the incoming particles, especially when the LET was 70 keV/um. When the LET was around 200 keV/um, the chromosome/DSB repair was almost fully inhibited irrespective of the kind of nuclides and the incoming energy. Our present study seems to substantiate the idea of complex or dirty DSB induced by high LET radiatIon. Although the number of induced chromosome breaks is low, the complex DNA damages would lead to substantially impaired initial part of NHEJ repair and eventual severe biological consequences.Our results provide useful insight on the initial stage of DNA DSB/chromosome damage and repair induced by high LET Heavy Ions.13th InternatIonal Congress of RadiatIon Researc
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Comparison of initial chromosome break repair in cells irradiated with high and low LET radiatIon
2019Co-Authors: Sekine Emiko, Okada Maki, Noguchi Miho, Yu Dong, Fujimori Akira, Okayasu RyuichiAbstract:The aim of this research is to determine the earliest biological effects at the chromosome level by high LET Heavy Ion radiatIon compared to those by X-rays in normal human cells (HFL III). We measured the number of chromosome breaks by the fusIon-induced premature chromosome condensatIon (PCC) assay. This assay is a cytogenetic method which can visualize chromosomes in inter-phase cells. As radiatIon sources, we used x-rays, carbon Ions (70 keV/um), neon Ions (70 keV/um, 200 keV/um), silicon Ions (70 keV/um, 200 keV/um), and iron Ions (200 keV/um). For all the PCC experiments, plateau cells (G0/G1 phase) were irradiated at 2Gy. In the process of fusIon-based PCC inductIon, cells have to be incubated at 37C, and the repair of DSBs can occur during this period. In order to detect chromosome breaks induced by irradiatIon at the earliest time point, we applied wortmannin (WM) to inhibit most of the DNA-PK dependent NHEJ type DSB repair during the incubatIon.In the case of X-rays about one half of the initial chromosome breaks were repaired, while almost no rejoining of initial breaks was observed in cells irradiated with silicon and iron particles. A correlatIon can be observed between the initial repair and the actual energy of the incoming particles, especially when the LET was 70 keV/um. When the LET was around 200 keV/um, the chromosome/DSB repair was almost fully inhibited irrespective of the kind of nuclides and the incoming energy. Our present study seems to substantiate the idea of complex or dirty DSB induced by high LET radiatIon. Although the number of induced chromosome breaks is low, the complex DNA damages would lead to substantially impaired initial part of NHEJ repair and eventual severe biological consequences.Our results provide useful insight on the initial stage of DNA DSB/chromosome damage and repair induced by high LET Heavy Ions.13th InternatIonal Congress of RadiatIon Researc
Nenoi Mitsuru - One of the best experts on this subject based on the ideXlab platform.
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Adaptive response and high-LET radiatIon
2019Co-Authors: Vares Guillaume, Bing Wang, Tanaka Kaoru, Murakami Masahiro, Kakimoto Ayana, Eguchi-kasai Kiyomi, Nenoi MitsuruAbstract:In contradictIon to classical paradigm, which assumes that radiatIon effects are directly proportIonal to energy deposit, numerous in vitro, in vivo and in utero studies described the existence in various models of a radiatIon-induced adaptive response (AR), according to which pre-exposure to low priming dose of Ionizing radiatIons decreases the biological effects of a subsequent higher challenging dose. Space radiatIons are both from solar and cosmic origin. Galactic cosmic rays (GCR) consist of high-charge and high-energy particles (C, Fe, H, He, N and O Ions), with an elevated relative biological efficiency (RBE). All these radiatIons can generate secondary radiatIons, such as neutrons and gamma-rays. Among the numerous problems that have to be resolved before considering long-term space journeys, exposure to high levels of cosmic rays would result in major health risks. Solar activity is highly fluctuating and unpredictable, and astronauts are susceptible to receive high amounts of radiatIon in a condensed time. Considering that chronic exposure of astronauts to space radiatIon could induce an AR and decrease their sensitivity to high radiatIon levels caused by solar activity, it is crucial to study in an adapted model the possibility of triggering an AR by such radiatIons. Furthermore, high-LET Heavy-Ion radiatIons produce non-randomly distributed DNA damage in the form of clusters, or locally multiply damaged sites (LMDS). In this research project, we tried to verify whether this kind of damage can trigger an "AR specific" DNA repair, and whether AR could protect against LMDS inductIon by challenging radiatIons.Biological effects of low and high-LET irradiatIon (performed at HIMAC, Chiba) were studied in three cultured human lymphoblastoid cell lines: TK6 (expressing wild-type p53 protein), AHH-1 (heterozygous for p53 expressIon) and NH32 (p53 knock-out). Cells were exposed to priming radiatIon, either X-Rays or Heavy-Ions, incubated for 6 hours, then exposed to challenging radiatIon at different LETs (X-Rays, Carbon-Ion: 15 and 40 keV.microm-1, Neon-Ion: 150 keV.microm-1). Resulting mutatIons frequencies (MF) at HPRT locus were measured. We also assessed cell cycle modulatIons, radiatIon-induced cell death and DNA double-strand break (DSB) inductIon and repair by studying ganma-H2AX phosphorylatIon kinetics using flow cytometry, within 48 hours after challenging irradiatIon.MF after challenging exposure was dependant on radiatIon LET, but surprisingly, carbon-Ion radiatIon at 40 keV.microM-1 had repeatedly a higher mutagenic effect than at a higher LET (40 keV.microM-1). Our results show that exposure to priming low doses of X-rays resulted in a significantly lower MF after high-LET challenging radiatIon. MF in cells primed with low-dose high-LET radiatIon in currently under investigatIon. No cell cycle modulatIon was observed after exposure to priming low dose. On the contrary, exposure to challenging dose resulted in an increased proportIon of cells in G2/M phase (G2 block), as expected. No difference was observed between adapted and non-adapted cells, suggesting that AR in this model is not related to cell cycle effects. gamma-H2AX phosphorylatIon levels peaked after priming and challenging radiatIon, and then decreased, reflecting the involvement of DNA DSB repair mechanisms. As observed previously, gamma-H2AX phosphorylatIon kinetics depended on LET. Interestingly, gamma-H2AX levels peaked earlier in TK6 adapted cells, suggesting that DSB repair might be involved in AR in this model.In conclusIon, our results suggested the existence of an adaptive response to mutagenic effects of Heavy-Ion radiatIon in lymphoblastoid cells, and pointed to a possible involvement of DSB repair mechanisms. The ability of high LET Heavy-Ion radiatIon (at low dose and low dose-rate) to induce AR is under investigatIon. Moreover, role of DSB repair will be evaluated by using siRNA specific to homologous recombinatIon and non-homologous end-joining proteins (respectively Rad54 and DNA-PKcs.The 7th Japan-France Workshop on RadiatIon Biolog
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High-LET Heavy-Ion RadiatIon and Adaptive Response
2019Co-Authors: Vares Guillaume, Bing Wang, Tanaka Kaoru, Kakimoto Ayana, Eguchi-kasai Kiyomi, Nenoi MitsuruAbstract:Adaptive response(AR) and bystander effect are two important phenomena involved in biological responses to low doses of Ionizing radiatIon(IR). Furthermore, there is a strong interest in better understanding the biological effects of high-LET radiatIon. In this study, we assessed in vitro the ability of priming low doses (0.01-0.1 Gy) of X-rays and Heavy-Ion radiatIon to induce an AR to a subsequent challenging dose (1-4Gy) of high-LET IR(carbon-Ion:20 and 40keV/mum, neon-Ion : 150keV/mum) in cultured lymphoblastoid TK6, AHH-1 and NH32 cells. Pre-exposure of p53-competent cells (both with low-dose X-rays and high-LET IR) resulted in decreased mutatIon frequencies at Hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus and different H2AX phosphorylatIon kinetics, as compared to cells exposed to challenging radiatIon alone. This phenominon was independent of radiatIon-induced apoptosis or cell cycle effects. Taken together, our results suggested the existence of an AR to mutagenic effects of Heavy-Ion radiatIon in lymphoblastoid cells and the involvement of double-strand break repair mechanisms.Even though the cell directly hit by Heavy-Ion beams (even at low doses) are likely to suffer significant damage, our results constitute the first report to date indicating that low doses of high-LET radiatIon can nevertherless induce protective effects against subsequent high-LET irradiatIon. Taking inter-individual varianbility into account, these results might have interesting implicatIons for high-LET radiatIon therapy and space research.日本放射線影響学会第５４回大
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Mutagenic adaptive response in human lymphoblastoid cells exposed to low and high-LET radiatIon
2019Co-Authors: Vares Guillaume, Bing Wang, Tanaka Kaoru, Murakami Masahiro, Kakimoto Ayana, Eguchi-kasai Kiyomi, Nenoi MitsuruAbstract:Exposure to low priming doses of Ionizing radiatIon is known to decrease the biological effects of a subsequent higher challenging dose. This adaptive response (AR) to low dose radiatIon was described in a variety of models, using various endpoints. In this study, we investigated the ability of low doses of X-rays to induce an AR to the biological effects of high-LET Heavy-Ion radiatIon (carbon-Ion, neon-Ion, 20 to 150 keV.um-1), in cultured human lymphoblastoid cells TK6 (p53 +/+) and AHH-1 (p53 +/-). We observed that cells adapted by X-rays showed a reduced mutatIon frequency at HPRT locus after exposure to high-LET radiatIon at HIMAC (NIRS, Chiba, Japan). AR in our model was dependent on p53 status but linked to neither cell cycle effects nor modulatIon of radiatIon-induced apoptosis. The analysis of H2AX phosphorylatIon kinetics in adapted and non adapted cells suggested that modulatIon of DNA double-strand break repair activity may be involved in this phenomenon. Knowing that high-LET radiatIon produces non-randomly distributed DNA damage in the form of clusters, or locally multiply damaged sites (LMDS), it seems that triggering AR by exposing cells to low doses of Ionizing radiatIon could protect cells against the detrimental effects of such damage新クロスオーバー国際シンポジウム、日本放射線影響学会第51回大
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Prospective study on adaptive response inductIon by Heavy-Ion radiatIon in human lymphoblastoid cell lines
2019Co-Authors: Vares Guillaume, Bing Wang, Tanaka Kaoru, Murakami Masahiro, Kakimoto Ayana, Eguchi-kasai Kiyomi, Nenoi MitsuruAbstract:In a variety of in vitro and in vivo models, pre-exposure to low priming dose of Ionizing radiatIons is well known to decrease the biological effects of a subsequent higher challenging dose. However, very few data exist concerning the possibility of inducing this phenomenon, called radiatIon-induced adaptive response (AR), when using high-LET accelerated Heavy-Ion radiatIon. In this study, cultured human lymphoblastoid cells (with different p53 status: TK6, AHH-1, NH32) were exposed to X-rays, carbon-Ion and neon-Ion radiatIon at various LETs (ranging from 20 to 150 keV/micrometer). MutatIon frequency at HPRT locus, radiatIon-induced cell death, cell cycle effects after irradiatIon, as well as estimatIon of DNA double-strand breaks inductIon and repair by measuring gamma-H2AX phosphorylatIon kinetics were compared in primed and unprimed cells. Our results suggest that the biological effects resulting from exposure to priming and challenging radiatIons vary according to irradiatIon type and LET. An AR to mutagenic effects of Heavy-Ion radiatIon at higher LET was observed when cells were exposed to priming doses of X-rays. The ability of low dose and low dose-rate Heavy-Ion radiatIon to trigger an AR was also assessed.日本放射線影響学会 第50回大
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Mechanisms underlying biological effects of low dose radiatIon: Mutagenic adaptive response to high-LET radiatIon in human lymphoblastoid cells
2019Co-Authors: Vares Guillaume, Bing Wang, Nenoi MitsuruAbstract:Recent developments in the low dose radiatIon research suggest that cellular response to low doses of Ionizing radiatIon (IR) cannot necessarily be directly extrapolated from responses to high doses [Mullenders, et al., Nat. Rev. Cancer. 9 (2009) 596-604, Averbeck, Health. Phys. 97 (2009) 493-504.]. Specific phenomena associated with low dose IR include bystander effect, low-dose hyper-radiosensitivity, genomic instability and adaptive response (AR). The ability of cells to adapt to low-dose or low-dose rate IR has been well documented both in vitro and in vivo, where pre-exposure of cells to low levels of radiatIon is responsible for decreased biological effects of challenging high doses [Vares, et al., Indian. J. Radiat. Res. 3 (2006) 16-34].High-LET radiatIon has unique characteristics, and the questIon of whether AR could be observed when using such radiatIon is of great interest for both the basic radiatIon research and the clinical fields. Unlike low-LET radiatIon, high-LET Heavy-Ion radiatIon produces non-randomly distributed DNA damage in the form of clusters, which are generally considered as non-easily repairable [Hada, et al., J. Radiat. Res. 49 (2008) 203-210]. Recent advances in cancer radiotherapy include the use of high-LET Heavy-Ion beams, which have over the last few years produced very promising clinical results. To date, not much is known about potential AR-related effects in relatIonship with high-LET radiatIon, let alone possible implicatIons of this phenomenon for radiatIon therapy. Space research is another field showing strong interest in high-LET-related radio-adaptatIon, because long-term space journeys would involve exposure to various kinds of high-LET radiatIon. The precise molecular mechanisms involved in AR remain elusive, but DNA repair and p53-related pathways are considered important effectors. It was suggested that repressIon of p53-dependent responses to radiatIon might be one of the mechanisms associated with AR, both in in vitro and in vivo models [Ohnishi, et al., Radiat. Res. 151 (1999) 368-372., Takahashi, et al., Int. J. Radiat. Biol. 77 (2001) 939-945]. Involvement of p53 pathways in AR might lead to the inductIon of several proteins associated with DNA repair, such as RAD51, RAD54 and BRCA1. The existence of an AR to mutatIon inductIon with low-LET radiatIon was demonstrated in different models, including lymphoblastoid cells, by several authors [Rigaud, et al., Mutat. Res. 358 (1996) 127 - 134., Hafer, et al., Radiat. Res. 168 (2007) 168-174., Lu, et al., Int. J. Radiat. Biol. 85 (2009) 532-537., Zhou, et al., Mutagenesis. 8 (1993) 109-111.]. They observed decreased mutatIon frequencies after irradiatIon when cells had previously been conditIoned by low doses of low-LET radiatIon.In this study, we assessed in vitro the ability of low doses of X-rays to induce an AR to a subsequent challenging dose of Heavy-Ion radiatIon. Lymphoblastoid cells (TK6, AHH-1, NH32) were exposed to priming 0.02-0.1 Gy X-rays, followed 6 hours later by challenging 1 Gy Heavy-Ion radiatIon (carbon-Ion: 20 and 40 keV/µm, neon-Ion: 150 keV/µm). Pre-exposure of p53-competent cells resulted in decreased mutatIon frequencies at Hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus and different H2AX phosphorylatIon kinetics, as compared to cells exposed to challenging radiatIon alone. This phenomenon did not seem to be linked with cell cycle effects or radiatIon-induced apoptosis. Taken together, our results suggested the existence of an AR to mutagenic effects of Heavy-Ion radiatIon in lymphoblastoid cells and the involvement of double-strand break repair mechanisms.ー放医研ワークショップー放射線医学・安全研究分野の国際展開に向けて-NIRS-Workshop as an IAEA CollaboratIong Centre
Yoshiya Shimada - One of the best experts on this subject based on the ideXlab platform.
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high relative biologic effectiveness of carbon Ion radiatIon on inductIon of rat mammary carcinoma and its lack of h ras and tp53 mutatIons
International Journal of Radiation Oncology Biology Physics, 2007Co-Authors: Tatsuhiko Imaoka, Mayumi Nishimura, Shizuko Kakinuma, Yukiko Hatano, Yasushi Ohmachi, Shinji Yoshinaga, Akihiro Kawano, Akihiko Maekawa, Yoshiya ShimadaAbstract:Purpose The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) Heavy-Ion radiatIon has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon Ion radiatIon and molecular changes that occur in the rat mammary cancer model. Methods and Materials We observed 7–8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiatIon (0.05–2 Gy) with either 290 MeV/u carbon Ions with a spread out Bragg peak (LET 40–90 keV/μm) generated from the Heavy-Ion Medical Accelerator in Chiba or 137 Cs γ-rays. Results Carbon Ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose–effect relatIonship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fractIon. In contrast, ∼10 should be considered for radiatIon protectIon at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor α. All carcinomas examined were free of common H- ras and Tp53 mutatIons. Importantly, lung metastasis (7%) was characteristic of carbon Ion–irradiated rats. ConclusIons We found clear genetic variability in the susceptibility to carbon Ion–induced mammary carcinomas. The high RBE for carbon Ion radiatIon further supports the importance of precise dose localizatIon in radiotherapy. Common point mutatIons in H- ras and Tp53 were not involved in carbon Ion inductIon of rat mammary carcinomas.
Gen Yang - One of the best experts on this subject based on the ideXlab platform.
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bystander abscopal effects induced in intact arabidopsis seeds by low energy Heavy Ion radiatIon
Radiation Research, 2008Co-Authors: Gen Yang, Tao Mei, Hang Yuan, Weiming Zhang, Lianyun Chen, Jianming Xue, Yugang WangAbstract:Abstract Yang, G., Mei, T., Yuan, H., Zhang, W., Chen, L., Xue, J., Wu, L. and Wang, Y. Bystander/Abscopal Effects Induced in Intact Arabidopsis Seeds by Low-Energy Heavy-Ion RadiatIon. Radiat. Res. 170, 372–380 (2008). To date, radiatIon-induced bystander effects have been observed largely in in vitro single-cell systems; verificatIon of both the effects and the mechanisms in multicellular systems in vivo is important. Previously we showed that bystander/ abscopal effects can be induced by irradiating the shoot apical meristem cells in Arabidopsis embryos. In this study, we investigated the in vivo effects induced by 30 keV 40Ar Ions in intact Arabidopsis seeds and traced the postembryonic development of both irradiated and nonirradiated shoot apical meristem and root apical meristem cells. Since the range of 30 keV 40Ar Ions in water is about 0.07 μm, which is less than the distance from the testa to shoot apical meristem and root apical meristem in Arabidopsis seeds (about 100 μm), the incident low-ene...
Akihiro Kawano - One of the best experts on this subject based on the ideXlab platform.
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high relative biologic effectiveness of carbon Ion radiatIon on inductIon of rat mammary carcinoma and its lack of h ras and tp53 mutatIons
International Journal of Radiation Oncology Biology Physics, 2007Co-Authors: Tatsuhiko Imaoka, Mayumi Nishimura, Shizuko Kakinuma, Yukiko Hatano, Yasushi Ohmachi, Shinji Yoshinaga, Akihiro Kawano, Akihiko Maekawa, Yoshiya ShimadaAbstract:Purpose The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) Heavy-Ion radiatIon has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon Ion radiatIon and molecular changes that occur in the rat mammary cancer model. Methods and Materials We observed 7–8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiatIon (0.05–2 Gy) with either 290 MeV/u carbon Ions with a spread out Bragg peak (LET 40–90 keV/μm) generated from the Heavy-Ion Medical Accelerator in Chiba or 137 Cs γ-rays. Results Carbon Ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose–effect relatIonship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fractIon. In contrast, ∼10 should be considered for radiatIon protectIon at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor α. All carcinomas examined were free of common H- ras and Tp53 mutatIons. Importantly, lung metastasis (7%) was characteristic of carbon Ion–irradiated rats. ConclusIons We found clear genetic variability in the susceptibility to carbon Ion–induced mammary carcinomas. The high RBE for carbon Ion radiatIon further supports the importance of precise dose localizatIon in radiotherapy. Common point mutatIons in H- ras and Tp53 were not involved in carbon Ion inductIon of rat mammary carcinomas.