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Development of a detection and evaluation system for carcinogens with the use of cell lines deficient in DNA repair genes

Research Project

Project/Area Number 12554035
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 遺伝
Research InstitutionFukuoka Dental College

Principal Investigator

ITOH Riyoko (2002)  Fukuoka Dental College, Dentistry, Research Associate, 歯学部, 助手 (10140865)

関口 睦夫 (2000-2001)  福岡歯科大学, 歯学部, 教授 (00037342)

Co-Investigator(Kenkyū-buntansha) TAKAGI Yasumitsu  Fukuoka Dental College, Dentistry, Assistant Professor, 歯学部, 助教授 (20212003)
下川 英俊  福岡歯科大学, 歯学部, 助手 (50122792)
伊東 理世子  福岡歯科大学, 歯学部, 助手 (10140865)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2001: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2000: ¥4,800,000 (Direct Cost: ¥4,800,000)
KeywordsDNA repair enzyme / O^6-methylguanine / tumorigenesis / mutation / cell line / gene deficient / anticancer agent / mouse / アポトーシス / 発ガン
Research Abstract

We have established a simple and accurate detection and evaluation system for carcinogens using cell lines from knockout mice, which are detective in the Mgmt gene encoding a DNA repair enzyme, O^6-methylguanine-DNA methyltransferase, and/or the Mlh1 gene encoding a protein involved in mismatch repair. Various cell lines were prepared by introduction of transforming vector, derived from SV40 virus, to primary cells isolated from lungs of mice with various genotypes, Mgmt^<-/->Mlh1^<+/+>, Mgmt^<-/->Mlh1^<-/->, Mgmt^<-/->Mlh1^<+/->, Mgmt^<+/+>Mlh1^<-/->. Mgmt^<-/->Mlh1^<+/+> cell line was hypersensitive to killing and mutation-inducing effects of methylnitrosourea (MNU), a simple alkylating agent. On the other hand, Mgmt^<-/->Mlh1^<-/-> cell line was as resistant to the killing effect of MNU as was wild cell line (Mgmt^<+/+>Mlh1^<+/+>), but MNU-induced mutant frequency of Mgmt^<-/->Mlh1^<-/-> cells was considerably higher than that of wild type cells. These results are consistent with killing and tumorigenic actions of MNU revealed with knockout mice. It is suggested that an increase in mutant frequency, caused by deficiency in DNA repair, would lead to tumor formation in organisms. To investigate whether this cell line system is useful for evaluation of therapeutic agents, we studied the killing and mutagenic effects of dacarbazine, which has alkylation potential. The results showed the same tendency as the case of MNU and effectiveness of this system is demonstrated. We are in progress to establish similar cell line systems for investigating spontaneous mutagenesis related to oxygen radicals, which can be produced through normal cellular metabolism.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Shimokawa, H.: "Functional significance of conserved residues in the hophohydrolase module of Escherichia coli MutT protein"Nucleic Acid Res.. 28. 3240-3249 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shiraishi, A.: "Increased susceptibility to chemotherapeutic alkylating agents of mice dificient in DNA repair methyltransferase"Carcinogenesis. 21. 1879-1883 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa, T.: "Importance of DNA repair in carsinogenesis : evidence from transgenic and gene targeting studies"Mutat. Res.. 477. 41-49 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuzuki, T.: "Spontaneous tumorigenesis in mice defective in the Mth1 gene encoding 8-oxo-dGTPase"Proc. Natl. Acad. Sci. U.S.A.. 98. 11456-11461 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsukura, S.: "Expression abd prognostic significance of O^6-methylguanine-DNA methyltransferase in hepatocellular, gastric, and breast cansers"Ann. Surg. Oncol.. 8. 807-816 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kohya, N.: "Deficient expression of O^6-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma"Ann. Surg. Oncol.. 9. 371-379 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimokawa, H.: "Functional significance of conserved residues in the phosphohydrolase module of Escherichia coli MutT protein"Nucleic Acid Res.. 28. 3240-3249 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shiraishi, A.: "Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase"Carcinogenesis. 21. 1879-1883 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa, T.: "Importance of DNA repair in carcinogenesis: evidence from transgenic and gene targeting studies"Mutat. Res.. 477. 41-49 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuzuki, T.: "Spontaneous tumorigenesis in mice defective in the Mth1 gene encoding 8-oxo-dGTPase"Proc. Natl. Acad. Sci. U.S.A.. 98. 11456-11461 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsukura, S.: "Expression and prognostic significance of O^6-methylguanine-DNA methyltransferase in hepatocellular, gastric, and breast cancers"Ann. Surg. Oncol.. 8. 807-816 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kohya, N.: "Deficient expression of O^6-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma"Ann. Surg. Oncol.. 9. 371-379 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuzuki, T.: "Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase"Proc.Natl.Acad.Sci.USA. 98. 1456-11461 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Liang, R.: "Presence of potential nickl-responsive element(s) in the mouse MTH1 promoter"Ann.Clin.Lab.Sci. 31. 91-98 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ishikawa, T.: "Importance of DNA repair in carcinogenesis : evidence from transgenic and gene targeting studies"Mutat.Res. 474. 41-49 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsukura, S.: "Expression and prognostic significance of O^6-methylguanine-DNA methyltransferase in hepatocelluar, gastric, and breast cancers"Ann.Surg.Onc. 8. 807-816 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kohya, N.: "Deficient expression of O^6-mehylguanine-DNA methyltransferase (MGMT) combined with mismatch repair protein hMLH1 and hMSH2 are related to poor prognosis in human biliary tract carcinoma"Ann.Surg.Onc. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Takahashi, M.: "Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein"J.Mol.Biol.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] R.Inoue: "Characterization of human polymorphic O^6-methylguanine DNA methyltransferase."Pharmacogenetics. 10. 59-66 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Kawate: "A defect in a single allele of the Mlh1 gene causes dissociation of killing and tumorigenic action of an alkylating carcunogen in methyltransferase-deficient mice."Carcinogenesis. 21. 301-305 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Miyako: "Accumulation of adenine DNA glycosylase-sensitive sites in human mitochondrial DNA."J.Biol.Chem.. 275. 12326-12330 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Shimokawa: "Functional significance of conserved residues in the phosphohydrolase module of Escherichia coli MutT protein."Nucl.Acids.Res.. 28. 3240-3249 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] A.Shiraishi: "Increased susceptibility of chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase"Carcinogenesis. 21. 1879-1883 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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