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Physiological and Clinical Implication of Metallothionein

Research Project

Project/Area Number 08044317
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field Biological pharmacy
Research InstitutionKITASATO UNIVERSITY

Principal Investigator

IMURA Nobumasa  Kitasato Univ., Pharmaceutical Sci., Professor, 薬学部, 教授 (70012606)

Co-Investigator(Kenkyū-buntansha) LAZO John.S.  Univ.of Pittsburgh, Sch.of Medicine, Professor, 医学部, 教授
KONDO Yukihiro  Nippon Medical School, Dept.of Urology, Assistant Professor, 医学部, 講師 (80215467)
NAGANUMA Akira  Tohoku Univ., Faculty of Pharmaceutical Sci., Professor, 薬学部, 教授 (80155952)
HIMENO Seiichiro  Kitasato Univ., Pharmaceutical Sci., Associate Professor, 薬学部, 助教授 (20181117)
LAZO John S  ピッツバーグ大学, 医学部, 教授
JOHN S. Laz  ピッツバーグ大学, 医学部, 教授
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1997: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1996: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsMetallothionein / Knockout mouse / Carcinogenesis / Heavy metal / Anticancer drug / Apoptosis
Research Abstract

1. To examine the protective role of physiological concentration of metallothionein (MT) against chemical carcinogenesis, MT-I and -II null (MTKO) and control (129/SV) mice were given N-butyl-N-4-hydroxybutyl nitrosamine (BBN) and the formation of bladder tumors were examined. The incidence of bladder tumor in MTKO mice was 72.9%, whereas 42.9% in 129/SV mice. Zn administration reduced the tumor incidence only in 129/SV mice. These data suggested that the baseline level of MT has protective role against chemical carcinogenesis.
2. SV40-transformed fibloblasts were obtained from both MTKO and 129/SV embryonic primary cultured cells. We established cisplatin-resistant and Cd-resistant MT null cells by gradual escalation of chemicals in the medium. Cisplatin-resistant MT null cells showed cross-resistance to Melphalan, paraquat and other ROI inducing agents. The cellular levels of thioredoxin and Ref-1, the latter molecule confers not only the redox regulation in the nucleus but blso the DNA repair by its endonuclease activity, were increased in cisplatin-resistant MT null cells. The accumulation of cisplatin as determined by Pt incorporation into the cells was lower in cisplatin-resistant MT null cells. Cd-resistant MT null cells also showed decreased accumulation of Cd compared to the parental MT null cells. The results of this study enabled further clarification of factors involved in cisplatin or Cd resistance other than MT.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] E.S Woo et al.: "Nucleophilic distribution of metallothionein in human tumor cells." Exp.Cell Res.224. 365-371 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Kondo et al.: "Enhanced apoptosis in metallothionein null cells." Mol.Pharmacol.52. 195-201 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Miyairi et al.: "Determination of metallothionein by high-performance liquid chromatography with fluorescence detection using an isocratic solvent system." Anal.Biochem.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] (in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] E.S.Woo, Y.Kondo, S.C.Watkins, D.G.Hoyt and J.S.Lazo: "Nucleophilic distribution of metallothionein in human tumor cells." Exp.Cell Res.224. 365-371 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Kondo, J.M.Rusnak, D.G.Hoyt, C.E.Settineri, B.R.Pitt and J.S.Lazo: "Enhanced apoptosis in metallothionein null cells." Mol.Pharmacol.52. 195-201 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] S.Miyairi, S.Shibata, and A.Naganuma: "Determination of metallothionein by high-performance liquid chromatography with fluorescence detection using an isocratic solvent system." Anal.Biochem.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kondo Y. et al.: "Enhanced apoptosis in metallothionein null cells." Mol. Pharmacol.52. 195-201 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakagawa, I. et al.: "Effect of glutathione depletion on metallothionein synthesis induced by paraquat in mice." Tohoku J. Exp. Med.177. 249-262 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nakagawa, I. et al,: "Effect of preinduction of metallothionein on clastogenicity of anticancer drugs in mice." Mutat. Res.348. 37-43 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nakagawa, I. et al.: "Induction of renal metallothionein synthesis by cis-diamminedichloroplatinum (II) in glutathione depleted mice." J. Trace Elements Exp. Med.8. 211-219 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Woo, E. S. et al.: "Nucleophilic distribution of metallothionein in human tumor cells" Exp. Cell Res.224. 365-371 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Rusnak, J. M. et al.: "Genesis of discrete higher order DNA fragments in apoptotic human prostatic carcinoma cells" Mol. Pharmacol.48. 244-252 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Lazo, J. S. et al.: "Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes." J. Biol. Chem.270. 5506-5510 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kondo, Y. et al.: "Metallothionein null cells have increased sensitivity to anticancer drugs." Cancer Res.55. 2021-2023 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kondo, Y. et al.: "Metallothionein localization and cisplatin resistance in human hormone-independent prostatic tumor cell lines." Cancer Res.55. 474-477 (1995)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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