Yoshiya Furusawa | National Institute of Radiological Sciences (original) (raw)
Papers by Yoshiya Furusawa
Journal of Radiation Research, 2014
The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of l... more The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable-conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.
Journal of Radiation Research, Dec 1, 1993
Journal of Radiation Research, Mar 31, 2009
ABSTRACT The efficacy of radiotherapy may be partly dependent on indirect effects, which can ster... more ABSTRACT The efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzylguanidine ([*I]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBqmL(-1) of the alpha-emitter meta-[211At]astatobenzylguanidine ([211At]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [131I]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [131I]MIBG and [131I]IUdR (low linear energy transfer (LET) beta-emitters) as well as [123I]MIBG and [123I]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [131I]MIBG- or [131I]IUdR-treated cells demonstrated a dose-response relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [123I]MIBG or [123I]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.
Journal of Radiation Research, Dec 1, 1993
Journal of Radiation Research, Dec 1, 2001
Journal of Radiation Research, Dec 15, 2003
![Research paper thumbnail of Intracellular reactions affecting 2-amino-4-([ 11C]methylthio)butyric acid ([ 11C]methionine) response to carbon ion radiotherapy in C10 glioma cells](https://attachments.academia-assets.com/46899626/thumbnails/1.jpg)
](Nucl Med Biol, 2009
The response of 2-amino-4-([14C]methylthio)butyric acid ([14C]Met) uptake and [125I]3-iodo-alpha-... more The response of 2-amino-4-([14C]methylthio)butyric acid ([14C]Met) uptake and [125I]3-iodo-alpha-methyl-l-tyrosine ([125I]IMT) uptake to radiotherapy of C10 glioma cells was compared to elucidate the intracellular reactions that affect the response of 2-amino-4-([11C]methylthio)butyric acid ([11C]Met) uptake to radiotherapy.After irradiation of cultured (3 Gy) or xenografted C10 glioma cells (25 Gy) using a carbon ion beam, the accumulation of [14C]Met and [125I]IMT in the tumors was investigated. The radiometabolites in xenografted tumors after radiotherapy were analyzed by size-exclusion HPLC.[14C]Met provided earlier responses to the carbon ion beam irradiation than [125I]IMT in both cultured and xenografted tumors. While [125I]IMT remained intact in xenografted tumor before and after irradiation, the radioactivity derived from [14C]Met was observed both in high molecular fractions and intact fractions, and the former decreased after irradiation.The earlier response of [11C]Met uptake to tumor radiotherapy could be attributable to the decline in the intracellular energy-dependent reactions of tumors due to radiotherapy.
Int J Radiat Oncol Biol Phys, 2008
To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion b... more To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion beams and reactor neutron beams. Squamous cell carcinoma VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine to label all intratumor proliferating cells. Next, they received accelerated carbon ion or gamma-ray high-dose-rate (HDR) or reduced-dose-rate (RDR) irradiation. Other tumor-bearing mice received reactor thermal or epithermal neutrons with RDR irradiation. Immediately after HDR and RDR irradiation or 12 h after HDR irradiation, the response of quiescent cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for 5-bromo-2'-deoxyuridine. The response of the total (proliferating plus quiescent) tumor cells was determined from the 5-bromo-2'-deoxyuridine nontreated tumors. The difference in radiosensitivity between the total and quiescent cell populations after gamma-ray irradiation was markedly reduced with reactor neutron beams or accelerated carbon ion beams, especially with a greater linear energy transfer (LET) value. Clearer repair in quiescent cells than in total cells through delayed assay or a decrease in the dose rate with gamma-ray irradiation was efficiently inhibited with carbon ion beams, especially with a greater LET. With RDR irradiation, the radiosensitivity to accelerated carbon ion beams with a greater LET was almost similar to that to reactor thermal and epithermal neutron beams. In terms of tumor cell-killing effect as a whole, including quiescent cells, accelerated carbon ion beams, especially with greater LET values, are very useful for suppressing the dependency on the heterogeneity within solid tumors, as well as depositing the radiation dose precisely.
Oncology Reports, Dec 1, 2006
The aim of this study was to identify potential biomarkers for radiosensitivity using the relatio... more The aim of this study was to identify potential biomarkers for radiosensitivity using the relationship between cell killing and the yield of excess chromatin fragments detected with the premature chromosome condensation (PCC) technique. This method was applied to primary cultured cells obtained from biopsies from patients. Six primary culture biopsies were obtained from 6 patients with carcinoma of the cervix before starting radiotherapy. The cultures were irradiated with two different LET carbon-ion beams (LET = 13 keV/μm, 77.1±2.8 keV/μm) and 200 kV X-rays. The carbon-ion beams were produced by Heavy Ion Medical Accelerator in Chiba (HIMAC). PCC was performed using the polyethylene glycolmediated cell fusion technique. The yield of excess chromatin fragments were measured by counting the number of unrejoined chromatin fragments detected with the PCC technique after a 24-h post-irradiation incubation period. Obtained results indicated that cultures which were more sensitive to killing were also more susceptible to the induction of excess chromatin fragments. Furthermore there was a good correlation between cell killing and excess chromatin fragments among the 6 cell cultures examined. There is also evidence that the induction of excess chromatin fragments increased with increasing LET as well as cell-killing effect in the same cell culture. The data reported here support the idea that the yield of excess chromatin fragments detected with the PCC technique might be useful for predicting the radiosensitivity of cells contained in tumor tissue, and to predict responses to different radiation types.
International Journal of Radiation Oncology Biology Physics, Aug 30, 1995
Purpose: To compare the biological effects of a 135 MeVlu carbon-ion beam and 13 MeV fast neutron... more Purpose: To compare the biological effects of a 135 MeVlu carbon-ion beam and 13 MeV fast neutron beaming human osteosarcoma cells. Methods and Materials: We have studied the clonogenic cell survival, recovery of potentially lethal damage (PLD) in plateau phase cells, and spheroid cure in multicellular spheropid after irradiation at various positions in the plateau and spread out Bragg peak (SOBP) of a 135 MeV/u carbon-ion beam and with 13 MeV neutrons. The carbon beam had a 4-cm range in water and a range filter was used to produce a 3cm extended-peak region. The reference radiation was '"Cs yrays. Results: The relative biological effectiveness (RBE) values for 10% survival level of plateau phase cells for carbon-ions at the position of plateau, proximal peak, midpeak, and distal peak within the SOBP, and neutrons were 1.71, 2.48, 2.63, 3.47, and 2.29, respectively. Corresponding RBE values at 1% level were 1.64,1.93,2.06,2.49, and 2.05. The extent of recovery from PLD was reduced after carbon-ions at proximal peak, midpeak, and distal peak, and neutrons, although not substantially reduced after carbon-ions at plateau. The RBE values for 50% spheroid cure level of spheroids for carbon-ions at the position of plateau, proximal peak, midproximal peak, middistal peak, and distal peak within the SOBP, and neutrons were 1.69, 1.88, 1.87, 1.94, 2.03, and 1.90, respectively. Conclusions: The biological parameters measured all indicate an approximately comparable biological effectiveness between 75-80 KeV/pm carbon-ions of the SOBP and 13 MeV neutrons in the human tumor model studied in vitro.
Journal of Radiation Research, Dec 1, 1997
Particle radiotherapy such as proton and carbon ion has been producing promising clinical results... more Particle radiotherapy such as proton and carbon ion has been producing promising clinical results worldwide. The purpose of this study was to compare metastatic capabilities of malignant tumor cells after irradiation with photon, proton, and carbon ion beams to clarify their ion beam-specific biological effects. We examined the biological properties of highly aggressive HT1080 human fibrosarcoma cells to assess their
Biological Pharmaceutical Bulletin, 2002
In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropropyl)-2-nitroimid... more In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropropyl)-2-nitroimidazole (4-BrFPN) was designed based on molecular orbital calculations, synthesized and labeled with fluorine-18 as a lipophilic nitroimidazole analog with a lower energy LUMO orbital than those for fluoromisonidazole (FMISO) and 1-(3-fluoropropyl)-2-nitroimidazole (FPN). In an in vitro radiosensitization study, the sensitizer enhancement ratio for 4-BrFPN was found to be 1.65 at a I mM concentration, in comparison to 1.81 for FMISO. The preparation of 18F-labeled 4-BrFPN (4-Br18FPN) was achieved by [18F]fluoride ion displacement reaction of the tosylate precursor, in a reasonable radiochemical yield (33%, not corrected for decay). Metabolites in tumor and muscle extracts from methylcholanthrene-induced fibrosarcoma mice, as well as the tissue distribution of 4-Br18FPN in normal rats, were studied. The initial uptake into rat brain of 4-Br18FPN was significantly higher relative to 18F-labeled FMISO (18FMISO), followed by a rapid washout from the brain. The tumor uptake of 4-Br18FPN was somewhat enhanced compared to those obtained with 18FMISO and 18F-labeled FPN (18FPN), but with lower tumor localization than 18FMISO. Analyses of tumor and muscle extracts showed metabolites remaining base line on the radio-TLC plates, and they were produced to a greater extent in tumor than muscle. The use of two drugs which increase hypoxic cell fraction in tumor, hydralazine or nitro-L-arginine, produced a significant increase in tumor levels of 4-Br18FPN, suggestive of a hypoxic mechanism of accumulation. The results imply that lowering of the LUMO energy of a molecule alone is not sufficient to improve its biodistribution properties for better imaging of regions of hypoxia.
Mutation Research Fundamental and Molecular Mechanisms of Mutagenesis, Mar 29, 2008
We investigated the earliest possible chromosome break and repair process in normal human fibrobl... more We investigated the earliest possible chromosome break and repair process in normal human fibroblasts irradiated with low and high LET (linear energy transfer) heavy ion radiation using the modified premature chromosome condensation (PCC) technique utilizing wortmannin (WM) during the fusion incubation period [M. Okada, S. Saito, R. Okayasu, Facilitated detection of chromosome break and repair at low levels of ionizing radiation by addition of wortannin to G1-type PCC fusion incubation, Mutat. Res., 562 (2004) 11-17]. The initial numbers of breaks were approximately 10/cell/Gy in X-irradiated samples, followed by carbon (LET: 70 keV/m), neon, and the number was around 5/cell/Gy in silicon (LET: 70 and 200 keV/m) and iron (LET: 200 keV/m) samples. If WM was not used, the initial numbers of breaks with silicon and iron were higher than those of X-rays. To quantify these data, we used initial repair ratio (IRR) defined as the number of G1 PCC breaks with WM divided by the number of breaks without WM. X-irradiation gave the maximum IRR (∼2.0), while iron as well as silicon irradiation showed the minimum IRR (∼1.0), suggesting almost no rejoining at the initial stage. Although there is a comparatively good correlation between the IRR value and the cell survival, the survival fraction with the repair data at 2 or 6 h correlates better statistically. Our data indicate that high LET heavy ion irradiation induces a lower number of initial chromosome breaks with minimal repair when compared with low LET irradiation. These results at the chromosome level substantiate and extend the notion that high LET radiation produces complex-type DNA double strand breaks (DSBs).
Journal of Radiation Research, Dec 15, 2003
Circulation Journal Official Journal of the Japanese Circulation Society, Mar 1, 2006
International Journal of Radiation Biology, Sep 1, 1998
To evaluate the relative biological effectiveness (RBE) of accelerated carbon ions generated with... more To evaluate the relative biological effectiveness (RBE) of accelerated carbon ions generated with a synchrotron for inducing mutations as a function of linear energy transfer (LET), using the loss of heterozygosity for wing-hair mutations and the reversion of the mutant white-ivory eye-colour in Drosophila melanogaster. The measurements were made using a combined mutation assay system so that induced mutant wing-hair clones as well as revertant eye-colour clones can be detected simultaneously in the same fly. Larvae were irradiated at the age of 72+/-6 h post-oviposition with X-rays or carbon ions with LET values of 13, 60 and 95 keV/microm. The RBE of carbon ions for producing wing-hair mosaic spots increased with increasing LET values. The RBE for the induction of eye-colour mutants did not change with LET. The estimated RBE values were found to be in the range 2 to 6.5 for the wing-hair and nearly unity for the eye-colour mosaic spot mutations. RBE-LET relationships were obtained for the induction of wing-hair and eye-colour mosaic spots. These relationships suggest that more complex types of DNA damage, such as nonrejoinable strand breaks that increase with LET, may be responsible for inducing the wing-hair mutation, while more simple forms of molecular damage induce reversion in the white-ivory allele.
Journal of Radiation Research, Dec 1, 2002
Journal of Radiation Research, 2014
The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of l... more The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable-conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.
Journal of Radiation Research, Dec 1, 1993
Journal of Radiation Research, Mar 31, 2009
ABSTRACT The efficacy of radiotherapy may be partly dependent on indirect effects, which can ster... more ABSTRACT The efficacy of radiotherapy may be partly dependent on indirect effects, which can sterilise malignant cells that are not directly irradiated. However, little is known of the influence of these effects in targeted radionuclide treatment of cancer. We determined bystander responses generated by the uptake of radioiodinated iododeoxyuridine ([*I]IUdR) and radiohaloanalogues of meta-iodobenzylguanidine ([*I]MIBG) by noradrenaline transporter (NAT) gene-transfected tumour cells. NAT specifically accumulates MIBG. Multicellular spheroids that consisted of 5% of NAT-expressing cells, capable of the active uptake of radiopharmaceutical, were sterilised by treatment with 20 kBqmL(-1) of the alpha-emitter meta-[211At]astatobenzylguanidine ([211At]MABG). Similarly, in nude mice, retardation of the growth of tumour xenografts containing 5% NAT-positivity was observed after treatment with [131I]MIBG. To determine the effect of subcellular localisation of radiolabelled drugs, we compared the bystander effects resulting from the intracellular concentration of [131I]MIBG and [131I]IUdR (low linear energy transfer (LET) beta-emitters) as well as [123I]MIBG and [123I]IUdR (high LET Auger electron emitters). [*I]IUdR is incorporated in DNA whereas [*I]MIBG accumulates in extranuclear sites. Cells exposed to media from [131I]MIBG- or [131I]IUdR-treated cells demonstrated a dose-response relationship with respect to clonogenic cell death. In contrast, cells receiving media from cultures treated with [123I]MIBG or [123I]IUdR exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighbouring untargeted cells at low and high dose respectively. It is concluded that radiopharmaceutical-induced bystander effects may depend on LET of the decay particles but are independent of site of intracellular concentration of radionuclide.
Journal of Radiation Research, Dec 1, 1993
Journal of Radiation Research, Dec 1, 2001
Journal of Radiation Research, Dec 15, 2003
Nucl Med Biol, 2009
The response of 2-amino-4-([14C]methylthio)butyric acid ([14C]Met) uptake and [125I]3-iodo-alpha-... more The response of 2-amino-4-([14C]methylthio)butyric acid ([14C]Met) uptake and [125I]3-iodo-alpha-methyl-l-tyrosine ([125I]IMT) uptake to radiotherapy of C10 glioma cells was compared to elucidate the intracellular reactions that affect the response of 2-amino-4-([11C]methylthio)butyric acid ([11C]Met) uptake to radiotherapy.After irradiation of cultured (3 Gy) or xenografted C10 glioma cells (25 Gy) using a carbon ion beam, the accumulation of [14C]Met and [125I]IMT in the tumors was investigated. The radiometabolites in xenografted tumors after radiotherapy were analyzed by size-exclusion HPLC.[14C]Met provided earlier responses to the carbon ion beam irradiation than [125I]IMT in both cultured and xenografted tumors. While [125I]IMT remained intact in xenografted tumor before and after irradiation, the radioactivity derived from [14C]Met was observed both in high molecular fractions and intact fractions, and the former decreased after irradiation.The earlier response of [11C]Met uptake to tumor radiotherapy could be attributable to the decline in the intracellular energy-dependent reactions of tumors due to radiotherapy.
Int J Radiat Oncol Biol Phys, 2008
To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion b... more To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion beams and reactor neutron beams. Squamous cell carcinoma VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine to label all intratumor proliferating cells. Next, they received accelerated carbon ion or gamma-ray high-dose-rate (HDR) or reduced-dose-rate (RDR) irradiation. Other tumor-bearing mice received reactor thermal or epithermal neutrons with RDR irradiation. Immediately after HDR and RDR irradiation or 12 h after HDR irradiation, the response of quiescent cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for 5-bromo-2'-deoxyuridine. The response of the total (proliferating plus quiescent) tumor cells was determined from the 5-bromo-2'-deoxyuridine nontreated tumors. The difference in radiosensitivity between the total and quiescent cell populations after gamma-ray irradiation was markedly reduced with reactor neutron beams or accelerated carbon ion beams, especially with a greater linear energy transfer (LET) value. Clearer repair in quiescent cells than in total cells through delayed assay or a decrease in the dose rate with gamma-ray irradiation was efficiently inhibited with carbon ion beams, especially with a greater LET. With RDR irradiation, the radiosensitivity to accelerated carbon ion beams with a greater LET was almost similar to that to reactor thermal and epithermal neutron beams. In terms of tumor cell-killing effect as a whole, including quiescent cells, accelerated carbon ion beams, especially with greater LET values, are very useful for suppressing the dependency on the heterogeneity within solid tumors, as well as depositing the radiation dose precisely.
Oncology Reports, Dec 1, 2006
The aim of this study was to identify potential biomarkers for radiosensitivity using the relatio... more The aim of this study was to identify potential biomarkers for radiosensitivity using the relationship between cell killing and the yield of excess chromatin fragments detected with the premature chromosome condensation (PCC) technique. This method was applied to primary cultured cells obtained from biopsies from patients. Six primary culture biopsies were obtained from 6 patients with carcinoma of the cervix before starting radiotherapy. The cultures were irradiated with two different LET carbon-ion beams (LET = 13 keV/μm, 77.1±2.8 keV/μm) and 200 kV X-rays. The carbon-ion beams were produced by Heavy Ion Medical Accelerator in Chiba (HIMAC). PCC was performed using the polyethylene glycolmediated cell fusion technique. The yield of excess chromatin fragments were measured by counting the number of unrejoined chromatin fragments detected with the PCC technique after a 24-h post-irradiation incubation period. Obtained results indicated that cultures which were more sensitive to killing were also more susceptible to the induction of excess chromatin fragments. Furthermore there was a good correlation between cell killing and excess chromatin fragments among the 6 cell cultures examined. There is also evidence that the induction of excess chromatin fragments increased with increasing LET as well as cell-killing effect in the same cell culture. The data reported here support the idea that the yield of excess chromatin fragments detected with the PCC technique might be useful for predicting the radiosensitivity of cells contained in tumor tissue, and to predict responses to different radiation types.
International Journal of Radiation Oncology Biology Physics, Aug 30, 1995
Purpose: To compare the biological effects of a 135 MeVlu carbon-ion beam and 13 MeV fast neutron... more Purpose: To compare the biological effects of a 135 MeVlu carbon-ion beam and 13 MeV fast neutron beaming human osteosarcoma cells. Methods and Materials: We have studied the clonogenic cell survival, recovery of potentially lethal damage (PLD) in plateau phase cells, and spheroid cure in multicellular spheropid after irradiation at various positions in the plateau and spread out Bragg peak (SOBP) of a 135 MeV/u carbon-ion beam and with 13 MeV neutrons. The carbon beam had a 4-cm range in water and a range filter was used to produce a 3cm extended-peak region. The reference radiation was '"Cs yrays. Results: The relative biological effectiveness (RBE) values for 10% survival level of plateau phase cells for carbon-ions at the position of plateau, proximal peak, midpeak, and distal peak within the SOBP, and neutrons were 1.71, 2.48, 2.63, 3.47, and 2.29, respectively. Corresponding RBE values at 1% level were 1.64,1.93,2.06,2.49, and 2.05. The extent of recovery from PLD was reduced after carbon-ions at proximal peak, midpeak, and distal peak, and neutrons, although not substantially reduced after carbon-ions at plateau. The RBE values for 50% spheroid cure level of spheroids for carbon-ions at the position of plateau, proximal peak, midproximal peak, middistal peak, and distal peak within the SOBP, and neutrons were 1.69, 1.88, 1.87, 1.94, 2.03, and 1.90, respectively. Conclusions: The biological parameters measured all indicate an approximately comparable biological effectiveness between 75-80 KeV/pm carbon-ions of the SOBP and 13 MeV neutrons in the human tumor model studied in vitro.
Journal of Radiation Research, Dec 1, 1997
Particle radiotherapy such as proton and carbon ion has been producing promising clinical results... more Particle radiotherapy such as proton and carbon ion has been producing promising clinical results worldwide. The purpose of this study was to compare metastatic capabilities of malignant tumor cells after irradiation with photon, proton, and carbon ion beams to clarify their ion beam-specific biological effects. We examined the biological properties of highly aggressive HT1080 human fibrosarcoma cells to assess their
Biological Pharmaceutical Bulletin, 2002
In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropropyl)-2-nitroimid... more In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropropyl)-2-nitroimidazole (4-BrFPN) was designed based on molecular orbital calculations, synthesized and labeled with fluorine-18 as a lipophilic nitroimidazole analog with a lower energy LUMO orbital than those for fluoromisonidazole (FMISO) and 1-(3-fluoropropyl)-2-nitroimidazole (FPN). In an in vitro radiosensitization study, the sensitizer enhancement ratio for 4-BrFPN was found to be 1.65 at a I mM concentration, in comparison to 1.81 for FMISO. The preparation of 18F-labeled 4-BrFPN (4-Br18FPN) was achieved by [18F]fluoride ion displacement reaction of the tosylate precursor, in a reasonable radiochemical yield (33%, not corrected for decay). Metabolites in tumor and muscle extracts from methylcholanthrene-induced fibrosarcoma mice, as well as the tissue distribution of 4-Br18FPN in normal rats, were studied. The initial uptake into rat brain of 4-Br18FPN was significantly higher relative to 18F-labeled FMISO (18FMISO), followed by a rapid washout from the brain. The tumor uptake of 4-Br18FPN was somewhat enhanced compared to those obtained with 18FMISO and 18F-labeled FPN (18FPN), but with lower tumor localization than 18FMISO. Analyses of tumor and muscle extracts showed metabolites remaining base line on the radio-TLC plates, and they were produced to a greater extent in tumor than muscle. The use of two drugs which increase hypoxic cell fraction in tumor, hydralazine or nitro-L-arginine, produced a significant increase in tumor levels of 4-Br18FPN, suggestive of a hypoxic mechanism of accumulation. The results imply that lowering of the LUMO energy of a molecule alone is not sufficient to improve its biodistribution properties for better imaging of regions of hypoxia.
Mutation Research Fundamental and Molecular Mechanisms of Mutagenesis, Mar 29, 2008
We investigated the earliest possible chromosome break and repair process in normal human fibrobl... more We investigated the earliest possible chromosome break and repair process in normal human fibroblasts irradiated with low and high LET (linear energy transfer) heavy ion radiation using the modified premature chromosome condensation (PCC) technique utilizing wortmannin (WM) during the fusion incubation period [M. Okada, S. Saito, R. Okayasu, Facilitated detection of chromosome break and repair at low levels of ionizing radiation by addition of wortannin to G1-type PCC fusion incubation, Mutat. Res., 562 (2004) 11-17]. The initial numbers of breaks were approximately 10/cell/Gy in X-irradiated samples, followed by carbon (LET: 70 keV/m), neon, and the number was around 5/cell/Gy in silicon (LET: 70 and 200 keV/m) and iron (LET: 200 keV/m) samples. If WM was not used, the initial numbers of breaks with silicon and iron were higher than those of X-rays. To quantify these data, we used initial repair ratio (IRR) defined as the number of G1 PCC breaks with WM divided by the number of breaks without WM. X-irradiation gave the maximum IRR (∼2.0), while iron as well as silicon irradiation showed the minimum IRR (∼1.0), suggesting almost no rejoining at the initial stage. Although there is a comparatively good correlation between the IRR value and the cell survival, the survival fraction with the repair data at 2 or 6 h correlates better statistically. Our data indicate that high LET heavy ion irradiation induces a lower number of initial chromosome breaks with minimal repair when compared with low LET irradiation. These results at the chromosome level substantiate and extend the notion that high LET radiation produces complex-type DNA double strand breaks (DSBs).
Journal of Radiation Research, Dec 15, 2003
Circulation Journal Official Journal of the Japanese Circulation Society, Mar 1, 2006
International Journal of Radiation Biology, Sep 1, 1998
To evaluate the relative biological effectiveness (RBE) of accelerated carbon ions generated with... more To evaluate the relative biological effectiveness (RBE) of accelerated carbon ions generated with a synchrotron for inducing mutations as a function of linear energy transfer (LET), using the loss of heterozygosity for wing-hair mutations and the reversion of the mutant white-ivory eye-colour in Drosophila melanogaster. The measurements were made using a combined mutation assay system so that induced mutant wing-hair clones as well as revertant eye-colour clones can be detected simultaneously in the same fly. Larvae were irradiated at the age of 72+/-6 h post-oviposition with X-rays or carbon ions with LET values of 13, 60 and 95 keV/microm. The RBE of carbon ions for producing wing-hair mosaic spots increased with increasing LET values. The RBE for the induction of eye-colour mutants did not change with LET. The estimated RBE values were found to be in the range 2 to 6.5 for the wing-hair and nearly unity for the eye-colour mosaic spot mutations. RBE-LET relationships were obtained for the induction of wing-hair and eye-colour mosaic spots. These relationships suggest that more complex types of DNA damage, such as nonrejoinable strand breaks that increase with LET, may be responsible for inducing the wing-hair mutation, while more simple forms of molecular damage induce reversion in the white-ivory allele.
Journal of Radiation Research, Dec 1, 2002