1998 Fiscal Year Annual Research Report

放射線感受性予測の基礎研究

Research Project

Project/Area Number	09255102
Research Institution	The University of Tokyo
Principal Investigator	鈴木紀夫東京大学, 大学院・医学系研究科, 教授 (10010050)
Co-Investigator(Kenkyū-buntansha)	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) 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)
Keywords	放射線感受性 / 先行指標 / 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
Research Abstract	1. 放射線感受性に関与する未知遺伝子の一つNBS(Nijmegen breakage syndrome)のcloningに成功した。 2. 変異導入p53遺伝子をLac Switch発現調節ベクターと共にSaos-2細胞(p53-/-)に導入し、発現させたときの放射線感受性変化(照射後の生存率、DNA断片化アポトーシス)の有無は変異導入部位に依存した。 3. 変異型p53悪性腫瘍細胞もglycerol処理でp53蛋白質の三次構造が変わり、正常型機能を示し、WAFlが誘導され、温熱感受性を回復しうることを見出した。 4. 精製したDNA-PKサブユニットを用いた実験から、温熱処理による放射線の増感作用がKu-サブユニットの熱不安定性のためであること、二相性のDNA二本鎖切断修復のうち早い修復系がDNA-PKに依存し、温熱処理により阻害されやすいことが判明した。 5. PI3キナーゼ阻害剤であるwortmanninはATM遺伝子産物及びDNA-PKの両活性を阻害して放射線を増感することが判明した。 6. 培養腫瘍細胞及び放治症例biopsyで照射10Gy程度の時点でFasの発現誘導が起こる場合があることや照射後のシグナル伝達経路の解明も一部進展した。 Micronucleus法にapoptosis指標を組合せることにより治療効果予測指標の実用性を高める検討も進展したが、今後、p53,ATM,DNA-PK,NBSや癌関連遺伝子(産物)の発現と放射線治療効果との関連をさらに解明する必要がある。放射線感受性に関する複数の機構が考えられ、シグナル伝達プロセスの解析及び、放射線感受性予測と感受性制御に結びつく遺伝子とその発現経路の解明を進める。

Research Products
(20 results)

All Other

All Publications (20 results)

[Publications] Matsumoto,Y.et al.: "A gelelectrophoretic analysis for improved sensitivity and specificity of DNA-dependent protein kinase activity." Radial.Res.(in press). (1999)
[Publications] Ishikawa,Y.et al.: "Partilion of thorium between organs of monkeys injected with Thorotrast:implications for alpha-particle dosimetry." Radiat.Res.,. 150. 369-372 (1998)
[Publications] Ohnishi,T.et al.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone." Radiat.Res.,. in press (1999)
[Publications] Ohnishi,K.et al.: "Contribution of protein kinase C to p53-dependent WAF1 induction pathway after heat treatment in human glioma cell lines." Exp.Cell Res.238. 399-406 (1998)
[Publications] LI-Hong Wang et al.: "Sensitivity of anticancer drugs in saos-2 cells transfected with mutant p53 variad with mutation point." Anticancer Res.18. 321-326 (1998)
[Publications] Okaichi,K.et al.: "Sensitivity to ionizing radiation in saos -2 cells transfected with mutant p53 gened depends on the mutation position." J.Radiat.Res.39. 111-118 (1998)
[Publications] Ihara,M.et al.: "Heat sensitivity of double-stranded DNA-dependent protein kinase(DNA-PK)activity." Int.J.Radiat.Biol.in press (1999)
[Publications] Ogwa,Y.et al.: "CD34-positive cell yield in peripheral blood of cancer patients during radiation therapy." Radiation Medicine,. 16. 37-41 (1998)
[Publications] Ogwa,Y.et al.: "Changes of mutant-type p53 expression in squamous cell carcinoma of the head and neck during radiation therapy and its clinical significance:Comparison of an immunohistochemical method and PCR-SSCP assay." Oncology Reports. 5. 1053-1059 (1998)
[Publications] Ogwa,Y.et al.: "Changes in telomerase activity of advanced cancers of oral cavity and oropharynex during radiation therapy:Correlation with clinical outcome." Int.J.Molecular Medicine. 2. 301-307 (1998)
[Publications] Matsuura,S.et al.: "Positional cloning of the gene for Nijmegen breakage syndrome." Nature Genetics. 19. 179-181 (1998)
[Publications] Hareyama,M.et al.: "The effect of radiation on the expression of intercellular adhesion molecule-1 of human adenocarcinoma cells." Int.J.Radiat.Oncol.Biol.Phys.40. 691-696 (1998)
[Publications] Suwa,T.et al.: "Inceased invasiveness of muc1-cDNA-transfected human gastric cancer MKN74 cells." Int.J.Cancer. 76. 377-382 (1998)
[Publications] Takaoka,A.et al.: "Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells." Jpn.J.Cancer Res.89. 397-404 (1998)
[Publications] Sasai,K.et al.: "Effects of SN-38(an active metabolite of CPT-11)on responses of human and rodent cells to irradiation." Int.J.Radiat.Oncol.Biol.Phys.42:(4). 785-788 (1998)
[Publications] Shibata,T.et al.: "Enhancement of gene expression under hypoxic conditions using fragment of the human vascular endothelial growth factor and the erythropoietin genes." Int.J.Radiat.Oncol.Biol.Phys.in press (1999)
[Publications] Takagi,T.et al.: "The influence of DNA ploidy of a human tumor cell line on the frequencies of micronuclei or chromosome aberrations after irradiation." Mut.Res.418. 49-57 (1998)
[Publications] Guo G.Z.et al.: "Simultaneous evaluation of radiation-induced apoptosis and micronuclei in five cell lines." Int.J.Radiat.Biol.73. 297-302 (1998)
[Publications] Hosoi,Y.et al.: "A phosphatidylionsitol 3-kinase inhibitor,wortmannin,induces radioresistant DNA synthesis,and sensitizes cells to bleomycin and ionizing radiation." Int.J.Cancer. 78. 642-647 (1998)
[Publications] Hosoi,Y.et al.: "Sensitization of cells to ionizing radiation by chlorin e6Na." Radiation Oncology Investigations. 6. 151-156 (1998)

1998 Fiscal Year Annual Research Report

放射線感受性予測の基礎研究

Principal Investigator

鈴木 紀夫 東京大学, 大学院・医学系研究科, 教授 (10010050)

Research Products

[Publications] Matsumoto,Y.et al.: "A gelelectrophoretic analysis for improved sensitivity and specificity of DNA-dependent protein kinase activity." Radial.Res.(in press). (1999)

[Publications] Ishikawa,Y.et al.: "Partilion of thorium between organs of monkeys injected with Thorotrast:implications for alpha-particle dosimetry." Radiat.Res.,. 150. 369-372 (1998)

[Publications] Ohnishi,T.et al.: "Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone." Radiat.Res.,. in press (1999)

[Publications] Ohnishi,K.et al.: "Contribution of protein kinase C to p53-dependent WAF1 induction pathway after heat treatment in human glioma cell lines." Exp.Cell Res.238. 399-406 (1998)

[Publications] LI-Hong Wang et al.: "Sensitivity of anticancer drugs in saos-2 cells transfected with mutant p53 variad with mutation point." Anticancer Res.18. 321-326 (1998)

[Publications] Okaichi,K.et al.: "Sensitivity to ionizing radiation in saos -2 cells transfected with mutant p53 gened depends on the mutation position." J.Radiat.Res.39. 111-118 (1998)

[Publications] Ihara,M.et al.: "Heat sensitivity of double-stranded DNA-dependent protein kinase(DNA-PK)activity." Int.J.Radiat.Biol.in press (1999)

[Publications] Ogwa,Y.et al.: "CD34-positive cell yield in peripheral blood of cancer patients during radiation therapy." Radiation Medicine,. 16. 37-41 (1998)

[Publications] Ogwa,Y.et al.: "Changes of mutant-type p53 expression in squamous cell carcinoma of the head and neck during radiation therapy and its clinical significance:Comparison of an immunohistochemical method and PCR-SSCP assay." Oncology Reports. 5. 1053-1059 (1998)

[Publications] Ogwa,Y.et al.: "Changes in telomerase activity of advanced cancers of oral cavity and oropharynex during radiation therapy:Correlation with clinical outcome." Int.J.Molecular Medicine. 2. 301-307 (1998)

[Publications] Matsuura,S.et al.: "Positional cloning of the gene for Nijmegen breakage syndrome." Nature Genetics. 19. 179-181 (1998)

[Publications] Hareyama,M.et al.: "The effect of radiation on the expression of intercellular adhesion molecule-1 of human adenocarcinoma cells." Int.J.Radiat.Oncol.Biol.Phys.40. 691-696 (1998)

[Publications] Suwa,T.et al.: "Inceased invasiveness of muc1-cDNA-transfected human gastric cancer MKN74 cells." Int.J.Cancer. 76. 377-382 (1998)

[Publications] Takaoka,A.et al.: "Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells." Jpn.J.Cancer Res.89. 397-404 (1998)

[Publications] Sasai,K.et al.: "Effects of SN-38(an active metabolite of CPT-11)on responses of human and rodent cells to irradiation." Int.J.Radiat.Oncol.Biol.Phys.42:(4). 785-788 (1998)

[Publications] Shibata,T.et al.: "Enhancement of gene expression under hypoxic conditions using fragment of the human vascular endothelial growth factor and the erythropoietin genes." Int.J.Radiat.Oncol.Biol.Phys.in press (1999)

[Publications] Takagi,T.et al.: "The influence of DNA ploidy of a human tumor cell line on the frequencies of micronuclei or chromosome aberrations after irradiation." Mut.Res.418. 49-57 (1998)

[Publications] Guo G.Z.et al.: "Simultaneous evaluation of radiation-induced apoptosis and micronuclei in five cell lines." Int.J.Radiat.Biol.73. 297-302 (1998)

[Publications] Hosoi,Y.et al.: "A phosphatidylionsitol 3-kinase inhibitor,wortmannin,induces radioresistant DNA synthesis,and sensitizes cells to bleomycin and ionizing radiation." Int.J.Cancer. 78. 642-647 (1998)

[Publications] Hosoi,Y.et al.: "Sensitization of cells to ionizing radiation by chlorin e6Na." Radiation Oncology Investigations. 6. 151-156 (1998)

鈴木紀夫東京大学, 大学院・医学系研究科, 教授 (10010050)