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Development of gene-mediated radiotherapy for tumors

Research Project

Project/Area Number 13470187
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Radiation science
Research InstitutionKyushu University

Principal Investigator

TSUZUKI Teruhisa  Kyushu University, Faculty of Medical Sciences, Professor, 大学院・医学研究院, 教授 (40155429)

Co-Investigator(Kenkyū-buntansha) KURA Shinobu  Kyushu University, Faculty of Medical Sciences, Research Associate, 大学院・医学研究院, 助手 (90037391)
NAKAMURA Katsumasa  Kyushu University, Faculty of Medical Sciences, Research Associate, 大学院・医学研究院, 助手 (20284507)
SASAKI Shigeki  Kyushu University, Faculty of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (10170672)
NAKATSU Yoshimichi  Kyushu University, Faculty of Medical Sciences, Associate Professor, 大学院・医学研究院, 助教授 (00207820)
MORITA Takashi  Osaka City University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (70150349)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥7,500,000 (Direct Cost: ¥7,500,000)
KeywordsDNA damage / DNA repair / Cell death / Synthetic oligomer / DNA recombination / Antigene / Radio sensitivity / Gene intervention / DNA組み換え
Research Abstract

Rad51 is a key component of the homologous recombination repair pathway. Previous experiments with the antisense oligonucleotides, designed to down-regulate Rad51 gene expression, resulted in leading to increased radiosensitivity of mouse glioma cell lines after high doses of radiation and an increased survival rate for glioma-bearing mice treated with the Rad51 antisense molecule prior to irradiation. As part of our efforts to devise strategies for enhancing the effectiveness of radiation therapy, we explored the use of RNAi(RNA interference) as a means of attenuating Rad51 expression in mouse teratocarcinoraa F9 cells in a gene therapy context. After transfection of the Rad51 siRNA(short interfering RNA), cells were cultured for two days, then irradiated by X-ray at a dose of 2 Gy. Radiosensitivity of the cells was analyzed,by MTT assay. The amount of Rad51 protein in Rad51 siRNA transfected cells was shown to approximately 30-40% of the level s expressed in control cells. The increased sensitivity of the cells to X-ray irradiation was evident when the cells were transfected with Rad51 siRNA, compared to mock-transfected cells. Furthermore, the effect of sensitization with Rad51 siRNA transfection was also observed when the cells were treated with an anti-tumor drug, cisplatin, which bind and break DNA. The concentration of cisplatin, which reduced cytotoxysicity to 50%, became 0.2μM from 0.4μM. Simultaneous exposure of the cells to X-ray irradiation and cisplatin exerted additive effect to the growth inhibition of F9 cells.
These results show the critical role of Rad51 in cellular responses to radiation as well as an anti-cancer drug, cisplatin, and indicate the potential use of Rad51-targeted RNAi in tumor radiosensitization.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Sakumi, K.et al.: "Ogg1-knockout-associated lung tumorigenesis and its suppression by the Mth1 gene disruption."Cancer Res.. 63. 902-905 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yoshida, K.et al.: "Expression and radiation-induced phosphorylation of histone H2AX in mammalian cells."J.Radiat.Res.. 44. 47-51 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamura, K.et al.: "Radical radiationtherapy for prostate cancer in Japan : A patterns of care study report."Jpn.J.Clin.Oncol.. 33. 122-126 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sasaki, S.et al.: "Selective formation of stable triplexs including a TA or a CG interrupting site with new bicyclic nucleoside analogs (WNA)."J.Amer.Chem.Soc.. 126. 516-528 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Habu, T.et al.: "P53 protein interacts specifically with the meiosis-specific mammalian RecA-like protein DMC1 in meiosis."Carcinogenesis. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shibahara, K.et al.: "Targeted disruption of one allele of the Y-box binding protein-1(YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin C."Cancer Sri.. 95. 348-353 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakumi, K. et al.: "Ogg1-knockout-associated lung tumorigenesis and its suppression by the Mth1 gene disruption."Cancer Res.. 63. 902-905 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yoshida, K et al.: "Expression and radiation -induced phosphorylation of histone H2AX in mammalian cells."J.Radiat.Res.. 44. 47-51 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamura, K. et al.: "Radical radiation therapy for prostate cancer in Japan : A patterns of care study report."Jpn.J.Clin.Oncol.. 33. 122-126 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sasaki, S. et al.: "Selective formation of stable triplex including a TA or a CG interrupting site with new bicyclic nucleoside analogs(WNA)."J.Amer.Chem.Soc.. 126. 516-528 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shibahara, K. et al.: "Targeted disruption of one allele of the Y-box binding protein-1(YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C."Cancer Sci.. 95. 348-353 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Habu, T. et al.: "P53 protein interacts specifically with the meiosis-specific mammalian RecA-like protein DMC1 in meiosis."Carcinogenesis. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakumi, K. et al.: "Ogg1-knockout-associated lung tumorigenesis and its suppression by the Mth1 gene disruption."Cancer Res.. 63. 902-905 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida, K. et al.: "Expression and radiation-induced phosphorylation of histone H2AX in mammalian cells."J.Radiat.Res.. 44. 47-51 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakamura, K. et al.: "Radical radiation therapy for prostate cancer in Japan : A patterns of care study report."Jpn.J.Clin.Oncol.. 33. 122-126 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki, S. et al.: "Selective formation of stable triplexes including a TA or a CG interrupting site with new bicyclic nucleoside analogs (WNA)."J.Amer.Chem.Soc.. 126. 516-528 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shibahara, K. et al.: "Targeted disruption of one allele of the Y-box binding-1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin..."Cancer Sci.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Habu, T. et al.: "P53 protein interacts specifically with the meiosis-specific mammalian RecA-like protein DMC1 in meiosis."Carcinogenesis. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Egashira A. et al.: "Mutational specificity of mice defective in the MTH1 and/or MSH2 genes"DNA Repair. 1・11. 881-893 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sekiguchi, M., Tsuzuki, T.: "Oxidative nucleotide damage : consequences and prevention"Oncogene. 21. 8895-8904 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Doi, T.et al.: "Induction of instability of p34(cdc2)ewpression by treatment with cisplatin (CDDP)in mouse teratocarcinoma F9 cells"Cancer Lett.. 176. 75-80 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamaguchi, K. et al.: "ERT following IORT improves survival of patients with respective pancreatic cancer"Gastroenterology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagatusgi, F. et al.: "Site-specific mutagenesis by triple-helix forming oligonucleotides containing a reactive nucleoside analogue"Nuclec Acids Res.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakumi, K. et al.: "Ogg1-knockout-associated lung tumorigenesis and its suppression by the Mth1 gene disruption"Cancer Res. 63(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Doi, T.et al.: "Induction of instability of p34 (cdc2) expression by treatment with cisplatin (CDDP) in mouse teratocarcinoma F9 cells"Cancer Lett. 176・1. 75-80 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuzuki, T. et al.: "Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase"Proc. Natl. Acad. Sci. USA. 98. 11456-11461 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuzuki, T. et al.: "Analysis of MTH1 gene function in mice with targeted mutagenesis"Mutat. Res. 477. 71-78 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sasaki, S.: "Active oligonucleotides incorporating alkylating agent as potential sequence-and base selective modifier of gene expression"Eur. J. Phar. Sci. 13・1. 43-51 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagatusugi, F. et al.: "A new reactive nucleotide analog for highly reactive and selective cross-linking reaction to cytidine under neutral conditions"Bioorg. & Med. Chem. Lett. 11・19. 2577-2579 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakamura, K. et al.: "Relapse pattern of localized non-Hodgkin's lymphoma of the head and neck after clinical remission : results of a strict follow-up procedure"Int. J. Clin. Oncol. 6. 302-305 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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