1999 年度実績報告書

放射線感受性予測の基礎研究

研究課題

研究課題/領域番号	09255102
研究機関	東京大学
研究代表者	鈴木紀夫東京大学, 大学院・医学系研究科, 教授 (10010050)
研究分担者	小松賢志広島大学, 原爆放射能医学研究所, 教授 (80124577) 奥村寛長崎大学, 医学部, 教授 (00073130) 大西武雄奈良県立医科大学, 医学部, 教授 (60094554) 平岡真寛京都大学, 大学院・医学研究科, 教授 (70173218) 小川恭弘高知医科大学, 医学部, 助教授 (90152397)
キーワード	放射線感受性 / 先行指導 / p53 / DNA-PK / NBS1 / 放射線誘導タンパク / 細胞死(アポトーシス) / 感受性修飾
研究概要	放射線による細胞死のメカニズムの解明とその感受性予測(治療法選択のための)への応用研究や感受性制御法の開発のための基礎研究がp53,DNA-PK,NBS1を中心に、シグナル伝達経路・細胞死過程への関与とその作用の解明について進展した。 NBS1は昨年までに遺伝子のクローニングが終わり、その機能について研究が進み、細胞周期制御への関与やそのC末側ドメインが感受性には重要であること、ATM/p53経由のシグナル伝達に関与していることが解明された。 p53に関しては、昨年までのデータに加えて、p53が感受性に関与する重要な因子になっている場合とその他の複数の因子が関与している場合について解明が進み、一層複雑となった。すなわち、p53が野生型か変異型かというだけでは予測に不十分で、他の複数の因子を含め判定することが必要である。一方、変異p53が抵抗性の原因となっている場合にはグリセロールやNaCl等で感受性を回復する可能性について基礎研究が進展した。 DNA-PKについては、従来から考えられているDNA二重鎖切断修復やシグナル伝達への関与のメカニズムに加え、DNA-PK(サブユニット)の変異株解析や各種細胞、特にゲッシ類細胞とヒト細胞の感受性比較検討から温熱感受性への関与についても研究が進展した。一方、DNA-PKをターゲットとした放射線感受性の制御についてはS-オリゴヌクレオチド,Wortmannin,温熱処理などによる可能性を示唆する結果が得られた。放射線の感受性に関与する重要因子について、解明が進むに従って、その因子の多いこと、また、メカニズムの複雑なことが判明しつつあり、治療法選択に有用な指標(群)や新しい感受性制御法の確立には多くの研究が必要である。

研究成果

(43件)

すべてその他

すべて文献書誌 (43件)

[文献書誌] Matsumoto, Y. et al.: "A gelelectrophoretic analysis for improved sensitivity and specificity of DNA-dependent protein kinase activity"J. Radiat. Res.. 40. 183-196 (1999)
[文献書誌] Kang, Y. et al.: "Increased expression after X-irradiation of MUC1 in cultured human colon carcinoma HT-29 cells"Jpn. J. Cancer Res.. (in press). (1999)
[文献書誌] Enomoto, A. et al.: "Involvement of SAPK/JNK pathway in X-ray-induced rapid cell death of human T-cell leukemia cell line MOLT-4"Cancer Lett.. (in press). (2000)
[文献書誌] Tomita, M. et al.: "Sensitization bywortmannin of heat or radiation induced cell death in cultured Chinese hamster V79 cells"J. Radiat. Res.. (in press). (2000)
[文献書誌] Ishikawa, Y. et al.: "Problems in histological diagnosis of cancer associated with chemo-and/or radiotherapy"J. Cancer Res. Clin. Oncol.. 125. 239-244 (1999)
[文献書誌] Takahashi, A. et al.: "The dependence of p53 on the radiation-enhancement thermosensitivity at different LET"Int. J. Radiat. Oncol. Biol. Phys.. (in press). (2000)
[文献書誌] Mima, T. et al.: "Early decrease of P-glyco-protein in the endothelium of the rat brain capillaries after moderate dose of irradiation"Neurological Research. 21. 209-215 (1999)
[文献書誌] Inomata, T. et al.: "Late pathologic changes in guinea pig kidneys irradiated with conventional fractionation and hyperfractionation"Int. J. Radiat. Oncol. Biol. Phys.. 44. 171-177 (1999)
[文献書誌] Nishioka, A. et al.: "The effects of nicotinamide plus carbogen or pions for microscopic SCCVII tumors"Oncology Reports. 6. 583-586 (1999)
[文献書誌] Nishioka, A. et al.: "Analysis of radiation pneumonitis and radiation-induced lung fibrosis in breast cancer patients after breast conservation treatment"Oncology Reports. 6. 513-517 (1999)
[文献書誌] Kariya, S. et al.: "X-irradiation enhances the expression of Bcl-2 in HL-60 cells : The resulting effects on apoptosis and radiosensitivity"Int. J. Mol. Med.. 3. 145-152 (1999)
[文献書誌] Nishioka, A. et al.: "An augmentation of Fas(CD95/APO-1) antigen induced by radiation : Flow cytometry analysis of lymphoma and leukemia cell lines"Int. J. Mol. Med.. 3. 275-278 (1999)
[文献書誌] Nakamura, A. et al.: "Four novel mutations of the Fanconi anemia group A gene (FAA) in Japanese patients"J. Hum. Genet.. 44. 48-51 (1999)
[文献書誌] Sakata, K. et al.: "Acceralated radiotherapy for T1,2 glottic carcinoma. Analysis of results with Ki 67 index."Int. J. Radiat. Oncol. Biol. Phys.. 45(in press). (2000)
[文献書誌] Ohnishi, T. et al.: "Heat-induced accumulation of p53 and hsp72 is suppressed in lung fibroblasts from SCID mice"Int. J. Radiat. Biol.. (in press). (2000)
[文献書誌] Harima, Y. et al.: "Bax and Bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIb cerevical carcinoma"Cancer. (in press). (2000)
[文献書誌] Takahashi, A. et al.: "WAF1 accumulation by carbon-ion beams and α-particle irradiation in human glioblastoma cultured cells"Int. J. Radiat. Biol.. (in press). (2000)
[文献書誌] Fujino, M. et al.: "Effects of protein kinase inhibitors on radiation-induced WAF1 accumulation in human cultured melanoma cells"British. J. Dermatol.. 141. 652-657 (1999)
[文献書誌] Inomata, T. et al.: "The immunopotentiation effects of the bifunctional radiosensitizer KIN-806 in comparison with its analogs KIN-804 and KIN-844"Oncology Reports. 6. 1209-1212 (1999)
[文献書誌] Inomata, T. et al.: "Lung metastasis suppression of the bifunctional new radiosensitizer KIN-806"Int. J. Mol. Med.. 4. 257-260 (1999)
[文献書誌] Itoh, S. et al.: "Serial histopathological changes in irradiated guinea pig lung receiving conventional fractionated and hyperfractionated irradiation"Radiation Medicine. 17. 227-233 (1999)
[文献書誌] Ogawa, Y. et al.: "Conservation treatment intensified with tamoxifen and CAF chemotherapy without axillary dissection for early breast cancer patients with clinically-negative axillary nodes"Oncology Reports. 6. 801-805 (1999)
[文献書誌] Guo GZ. et al.: "A significant correlation between clonogenic radiosensitivity and the simultaneous assessment of micronucleus and apoptotic cell frequencies"Int. J. Radiat. Biol.. 75(7). 857-864 (1999)
[文献書誌] Shibuya, K. et al.: "Detection of hypoxic cells in murine tumors using the comet assay : Comparison with a conventional radiobiological assay"Jpn. J. Cancer Res.. 90(8). 880-886 (1999)
[文献書誌] Xie X. et al.: "P53 status plays no role in radiosensitizing effects of SN-38, a camptothecin derivave"Cancer Chemother Pharmacol.. (in press). (2000)
[文献書誌] Kanamori, S. et al.: "Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesisinhibitor"Int. J. Hyperthermia. 15(4). 267-278 (1999)
[文献書誌] Okuno, Y. et al.: "Prognostic values of proliferating cell nuclear antigen (PCNA) and Ki-67 for radiotherapy of oesophageal squamous cell carcinomas"Br. J. Cancer. 80(3-4). 287-295 (1999)
[文献書誌] Ono, T. et al.: "Molecular Nature of mutations induced by a high dose of X-rays in spleen, liver, and brain of the lacZ-transgenic mouse"Environmental and Molecular Mutagenesis. 34. 97-105 (1999)
[文献書誌] Nakamura, S. et al.: "Radiation-induced mutation in spleen and brain of plasmid-based lacZ transgenic mouse"Int. J. Radiat. Biol.. (in press). (2000)
[文献書誌] Zhao, H. -J. et al.: "DNA-dependent protein kinase activity correlates with Ku70 expression and radiation sensitivity in esophageal cancer cell lines"Clinical Cancer Res.. (in press). (2000)
[文献書誌] Ogawa, Y. et al.: "Ionizing radiation-induced apoptosis in human lymphoma cell lines differing in p53 status"Int. J. Mol. Med.. (in press). (2000)
[文献書誌] Harima, Y. et al.: "Genetic alterations on chromosome 17p associated with response to radiotherapy in bulky cerevical cancer"Brit. J. Cancer. 81. 108-113 (1999)
[文献書誌] Tamamoto, T. et al.: "Correlation between gamma-ray-induced G2 arrest and radioresistance in two human melanomas"Int. J. Radiat. Oncol. Biol. Phys.. 44. 905-909 (1999)
[文献書誌] Ohnishi, T. et al.: "Restoration of p53-dependent apoptosis in the cells bearing the mutant p53 gene by glycerol"Int. J. Radiat. Biol.. 75. 1095-1098 (1999)
[文献書誌] Ohnishi, T. et al.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone"Radiat. Res.. 151. 498-500 (1999)
[文献書誌] Ohnishi, K. et al.: "The protein kinase inhibitor, H-7, suppresses heat-induced activation of heat shock transcription factor 1"Mol. Cell. Biochem.. 197. 129-135 (1999)
[文献書誌] Ohnishi, T. et al.: "Low-dose-rate radiation attenuates the response of the tumor suppressor TP53"Radiat. Res.. 151. 368-372 (1999)
[文献書誌] Okaichi, K. et al.: "A point mutation of human p53, which was not detected as a mutation by a yeast functional assay, led to apoptosis but not p21 Waf-1/Clip 1/S dil expression in response to ionizing radiation in a human osteosarocoma cell line, Saos-2"Int. J. Radiat. Oncol. Biol. Phys.. 45. 975-980 (1999)
[文献書誌] Ihara, M. et al.: "Heat sensitivity of double-strand DNA-dependent protein kinase (DNA-PK) activity"Int. J. Radiat. Biol.. 75. 253-258 (1999)
[文献書誌] Ito, A. et al.: "Expression of full-length NBS1 protein restores normal radiation responses in cells from Nijmegen Breakage Syndrome patients"Biochem. Biophys. Res. Commun.. 265. 716-721 (1999)
[文献書誌] Hiramoto, T. et al.: "Mutations of a novel human RAD54 homologue, in primary cancer"Oncogene. 18. 3422-3426 (1999)
[文献書誌] Tauchi, H. et al.: "Sequence analysis of an 800-kb genomic DNA-region on chromosome 8q21, which contains the Nijmegen breakage syndrome gene, NBS1"Genomics. 55. 242-247 (1999)
[文献書誌] Morishita, K. et al.: "A polymorphic CA repeat marker at the human 27kD-clbindin(CALB1) locus"J. Hum. Genet.. 44. 414-415 (1999)

1999 年度 実績報告書

放射線感受性予測の基礎研究

研究代表者

鈴木 紀夫 東京大学, 大学院・医学系研究科, 教授 (10010050)

研究成果

[文献書誌] Matsumoto, Y. et al.: "A gelelectrophoretic analysis for improved sensitivity and specificity of DNA-dependent protein kinase activity"J. Radiat. Res.. 40. 183-196 (1999)

[文献書誌] Kang, Y. et al.: "Increased expression after X-irradiation of MUC1 in cultured human colon carcinoma HT-29 cells"Jpn. J. Cancer Res.. (in press). (1999)

[文献書誌] Enomoto, A. et al.: "Involvement of SAPK/JNK pathway in X-ray-induced rapid cell death of human T-cell leukemia cell line MOLT-4"Cancer Lett.. (in press). (2000)

[文献書誌] Tomita, M. et al.: "Sensitization bywortmannin of heat or radiation induced cell death in cultured Chinese hamster V79 cells"J. Radiat. Res.. (in press). (2000)

[文献書誌] Ishikawa, Y. et al.: "Problems in histological diagnosis of cancer associated with chemo-and/or radiotherapy"J. Cancer Res. Clin. Oncol.. 125. 239-244 (1999)

[文献書誌] Takahashi, A. et al.: "The dependence of p53 on the radiation-enhancement thermosensitivity at different LET"Int. J. Radiat. Oncol. Biol. Phys.. (in press). (2000)

[文献書誌] Mima, T. et al.: "Early decrease of P-glyco-protein in the endothelium of the rat brain capillaries after moderate dose of irradiation"Neurological Research. 21. 209-215 (1999)

[文献書誌] Inomata, T. et al.: "Late pathologic changes in guinea pig kidneys irradiated with conventional fractionation and hyperfractionation"Int. J. Radiat. Oncol. Biol. Phys.. 44. 171-177 (1999)

[文献書誌] Nishioka, A. et al.: "The effects of nicotinamide plus carbogen or pions for microscopic SCCVII tumors"Oncology Reports. 6. 583-586 (1999)

[文献書誌] Nishioka, A. et al.: "Analysis of radiation pneumonitis and radiation-induced lung fibrosis in breast cancer patients after breast conservation treatment"Oncology Reports. 6. 513-517 (1999)

[文献書誌] Kariya, S. et al.: "X-irradiation enhances the expression of Bcl-2 in HL-60 cells : The resulting effects on apoptosis and radiosensitivity"Int. J. Mol. Med.. 3. 145-152 (1999)

[文献書誌] Nishioka, A. et al.: "An augmentation of Fas(CD95/APO-1) antigen induced by radiation : Flow cytometry analysis of lymphoma and leukemia cell lines"Int. J. Mol. Med.. 3. 275-278 (1999)

[文献書誌] Nakamura, A. et al.: "Four novel mutations of the Fanconi anemia group A gene (FAA) in Japanese patients"J. Hum. Genet.. 44. 48-51 (1999)

[文献書誌] Sakata, K. et al.: "Acceralated radiotherapy for T1,2 glottic carcinoma. Analysis of results with Ki 67 index."Int. J. Radiat. Oncol. Biol. Phys.. 45(in press). (2000)

[文献書誌] Ohnishi, T. et al.: "Heat-induced accumulation of p53 and hsp72 is suppressed in lung fibroblasts from SCID mice"Int. J. Radiat. Biol.. (in press). (2000)

[文献書誌] Harima, Y. et al.: "Bax and Bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIb cerevical carcinoma"Cancer. (in press). (2000)

[文献書誌] Takahashi, A. et al.: "WAF1 accumulation by carbon-ion beams and α-particle irradiation in human glioblastoma cultured cells"Int. J. Radiat. Biol.. (in press). (2000)

[文献書誌] Fujino, M. et al.: "Effects of protein kinase inhibitors on radiation-induced WAF1 accumulation in human cultured melanoma cells"British. J. Dermatol.. 141. 652-657 (1999)

[文献書誌] Inomata, T. et al.: "The immunopotentiation effects of the bifunctional radiosensitizer KIN-806 in comparison with its analogs KIN-804 and KIN-844"Oncology Reports. 6. 1209-1212 (1999)

[文献書誌] Inomata, T. et al.: "Lung metastasis suppression of the bifunctional new radiosensitizer KIN-806"Int. J. Mol. Med.. 4. 257-260 (1999)

[文献書誌] Itoh, S. et al.: "Serial histopathological changes in irradiated guinea pig lung receiving conventional fractionated and hyperfractionated irradiation"Radiation Medicine. 17. 227-233 (1999)

[文献書誌] Ogawa, Y. et al.: "Conservation treatment intensified with tamoxifen and CAF chemotherapy without axillary dissection for early breast cancer patients with clinically-negative axillary nodes"Oncology Reports. 6. 801-805 (1999)

[文献書誌] Guo GZ. et al.: "A significant correlation between clonogenic radiosensitivity and the simultaneous assessment of micronucleus and apoptotic cell frequencies"Int. J. Radiat. Biol.. 75(7). 857-864 (1999)

[文献書誌] Shibuya, K. et al.: "Detection of hypoxic cells in murine tumors using the comet assay : Comparison with a conventional radiobiological assay"Jpn. J. Cancer Res.. 90(8). 880-886 (1999)

[文献書誌] Xie X. et al.: "P53 status plays no role in radiosensitizing effects of SN-38, a camptothecin derivave"Cancer Chemother Pharmacol.. (in press). (2000)

[文献書誌] Kanamori, S. et al.: "Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesisinhibitor"Int. J. Hyperthermia. 15(4). 267-278 (1999)

[文献書誌] Okuno, Y. et al.: "Prognostic values of proliferating cell nuclear antigen (PCNA) and Ki-67 for radiotherapy of oesophageal squamous cell carcinomas"Br. J. Cancer. 80(3-4). 287-295 (1999)

[文献書誌] Ono, T. et al.: "Molecular Nature of mutations induced by a high dose of X-rays in spleen, liver, and brain of the lacZ-transgenic mouse"Environmental and Molecular Mutagenesis. 34. 97-105 (1999)

[文献書誌] Nakamura, S. et al.: "Radiation-induced mutation in spleen and brain of plasmid-based lacZ transgenic mouse"Int. J. Radiat. Biol.. (in press). (2000)

[文献書誌] Zhao, H. -J. et al.: "DNA-dependent protein kinase activity correlates with Ku70 expression and radiation sensitivity in esophageal cancer cell lines"Clinical Cancer Res.. (in press). (2000)

[文献書誌] Ogawa, Y. et al.: "Ionizing radiation-induced apoptosis in human lymphoma cell lines differing in p53 status"Int. J. Mol. Med.. (in press). (2000)

[文献書誌] Harima, Y. et al.: "Genetic alterations on chromosome 17p associated with response to radiotherapy in bulky cerevical cancer"Brit. J. Cancer. 81. 108-113 (1999)

[文献書誌] Tamamoto, T. et al.: "Correlation between gamma-ray-induced G2 arrest and radioresistance in two human melanomas"Int. J. Radiat. Oncol. Biol. Phys.. 44. 905-909 (1999)

[文献書誌] Ohnishi, T. et al.: "Restoration of p53-dependent apoptosis in the cells bearing the mutant p53 gene by glycerol"Int. J. Radiat. Biol.. 75. 1095-1098 (1999)

[文献書誌] Ohnishi, T. et al.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone"Radiat. Res.. 151. 498-500 (1999)

[文献書誌] Ohnishi, K. et al.: "The protein kinase inhibitor, H-7, suppresses heat-induced activation of heat shock transcription factor 1"Mol. Cell. Biochem.. 197. 129-135 (1999)

[文献書誌] Ohnishi, T. et al.: "Low-dose-rate radiation attenuates the response of the tumor suppressor TP53"Radiat. Res.. 151. 368-372 (1999)

[文献書誌] Ihara, M. et al.: "Heat sensitivity of double-strand DNA-dependent protein kinase (DNA-PK) activity"Int. J. Radiat. Biol.. 75. 253-258 (1999)

[文献書誌] Ito, A. et al.: "Expression of full-length NBS1 protein restores normal radiation responses in cells from Nijmegen Breakage Syndrome patients"Biochem. Biophys. Res. Commun.. 265. 716-721 (1999)

[文献書誌] Hiramoto, T. et al.: "Mutations of a novel human RAD54 homologue, in primary cancer"Oncogene. 18. 3422-3426 (1999)

[文献書誌] Tauchi, H. et al.: "Sequence analysis of an 800-kb genomic DNA-region on chromosome 8q21, which contains the Nijmegen breakage syndrome gene, NBS1"Genomics. 55. 242-247 (1999)

[文献書誌] Morishita, K. et al.: "A polymorphic CA repeat marker at the human 27kD-clbindin(CALB1) locus"J. Hum. Genet.. 44. 414-415 (1999)

1999 年度実績報告書

鈴木紀夫東京大学, 大学院・医学系研究科, 教授 (10010050)