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Studies on the elucidation of the enhanced mechanism of chemical carcinogenesis

Research Project

Project/Area Number 09660348
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied veterinary science
Research InstitutionNational Institute of Health Sciences

Principal Investigator

MITSUMORI Kunitoshi  Div.of Pathology, National Institute of Health Sciences Section Head, 病理部, 室長 (10239296)

Co-Investigator(Kenkyū-buntansha) YASUHARA Kazuo  Div.Of Pathol, National Institute of Health Sciences Senior Scientist, 病理部, 主任研究官 (80174522)
ONODERA Hiroshi  Div.Of Pathol, National Institute of Health Sciences Senior Scientisit, 病理部, 主任研究官 (60177285)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordstransgenic mice / rasH2 mice / p53 deficient mice / human prototype c-Ha-ras gene / p53 supressor oncogene / rasH2マウス / p53ノックアウトマウス / ヒトプロト型c-Ha-ras遺伝子 / p53癌抑制遺伝子 / 前胃腫瘍 / 皮膚腫瘍 / 膀胱腫瘍 / 肝腫瘍 / K-ras遺伝子 / 肺腫瘍 / 子宮腫瘍
Research Abstract

To clarify the mechanism of the enhancement of carcinogenesis by the treatment of genotoxic carcinogens in transgenic mice, the following experiments were performed : (1) Transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) and their wild littermates (non-Tg mice) received an intraperitoneal (ip) injection of urethane. Lung adenomas with high frequency of point mutations of the transgene were induced in treated rasH2 mice. (2) Heterozygous p53 deficient CBA mice [p53 (+/-) CBA mice] and their wold littermates {p53 (+/+) mice] received an ip injection of ethylnitrosourea (ENU). Uterine tumors with high frequency of point mutations of p53 were induced in treated p53 (+/-) mice. The results suggest that point mutations of p53 are responsible for the induction of uterine tumors. (3) Diet containing of p-cresidine was given to rasH2 and non-Tg mice for 26 weeks. Transitional cell papillomas and carcinomas were frequently induced in treated rasH2 mice, but point mutations of the transgene were not related to the tumor induction. (4) p53 (+/-) and p53 (+/+) CBA mice received an ip injection of dimethylnitrosamine (DMN) followed by phenobarbital (PB) for 26 weeks. The incidence of hepatocellular adenomas was significantly increased in p53 (+/-) mice of the DMN+PB group as compared to that in p53 (+/+) mice, but no point mutations of p53 were observed in the induced tumors. (5) Glandular stomach tumors are induced I p53 (+/-) TSG mice by the treatment of methylnitrosourea (MNU) for 10 weeks, but no data were available in p53 (+/-) CBA mice. Therefore, p53 (+/-) and p53 (+/+) CBA mice were given water containing MNU for 26 weeks. The fact that no glandular stomach tumors were induced in these treated mice suggests that the carcinogenic susceptibility is different even in the same p53 (+/-) mice depending on the strain difference or different genetically engineering procedures.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Mitsumori,K.,: "Pulmonary fibrosis caused by N-mrthyl-N-nitrosourethane inhibits lung tumorigenesis by urethane in transgenic mice carrying the human prorotype c-Ha-ras gene."Cancer Letters. 129. 181-190 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori,K.,: "Rapid induction of Uterine tumors with p53 point mutations in heterozygous p53-deficient CBA mice given a single intraperitoneal administration of N-ethyl-N-nitrosourea."Carcinogenesis. 21. 1039-1042 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori,K.,: "Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies."Toxicologic Pathology. 26. 520-531 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Maronpot,R.R.,: "Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model."Toxicology. 146. 149-159 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takagi,H.,Mitsumori,K.,: "Lack of carcinogenic sensitivity of the glandular stomach in heterozygous p53 deficient mice given N-mrthyl-N-nitrosourea in drinking water for 26 weeks."Asian Pacific J.Cancer Prevention. 1. 299-303 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori,K.: "Assessment of Pharmaceuticals for Potential Human Carcinogenic Risk"Center for Medicines Research International. 12 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori, K., Yasuhara, K., Mori, I., Hayashi, S., Shimo, T., Onodera, H., Nomura, T.and Hayashi, Y.: "Pulmonary fibrosis caused by N-methyl-N-nitrosourethane inhibits lung tumorigenesis by urethane in transgenic mice carrying the human prorotype c-Ha-ras gene."Cancer Letters. 129. 181-190 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori, K., Onodera, H., Shimo, T., Yasuhara, K., Takagi, H., Koujitani, K., Hirose, M., Maruyama, C.and Wakana, S.: "Rapid induction of Uterine tumors with p53 point mutations in heterozygous p53-deficient CBA mice given a single intraperitoneal administration of N-ethyl-N-nitrosourea."Carcinogenesis. 21. 1039-1042 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori, K., Koizumi, H., Nomura, T.and Yamamoto, S.: "Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies."Toxicol. Pathol.. 26. 520-531 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Maronpot, R.R, Mitsumori, K., Mann, P., Takaoka, M., Yamamoto, S., Usui, T., Okamiya, H., Nishikawa, S.and Nomura, T.: "Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model."Toxicol ogy. 146. 149-159 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takagi, H., Onodera, H., Yasuhara, K., Koujitani, T., Tamura, T., Hirose, M.and Mitsumori, K.: "Lack of carcinogenic sensitivity of the glandular stomach in heterozygous p53 deficient mice given N-methyl-N-nitrosourea in drinking water for 26 weeks."Asian Pacific J.Cancer Prevent.. 1. 299-303 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mitsumori K.: "Induction of Uterine tumors with p53 point mutations in female p53 deficient CBA mice given a single administration of N-ethyl-N-nitrosourea"Carcinogenesis. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Koujitani T.: "Lack of susceptibility of transgenic mice carrying the human prototype c-Ha-ras gene(rasH2 mice)in a six-month carcinogenicity study of phenolphtalein"Cancer Letters. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maronpot R.R.: "Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model"Toxicology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mitsumori K.: "Assessment of Pharmaceuticals for Potential Human Carcinogenic Risk"Center for Medicines Research International. 12 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Mitsumori: "Pathological features of spontaneous and induced tumors in transgenic mice carrying human prototype c-Ha-ras gene used for 6-month carcinogenicity studies" Toxicologic Pathdogy. 26巻. 520-531 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] S.Yamamoto: "Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing" Environmental Health Perspective. 106巻追加1号. 57-69 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Mitsumori: "Pretreatment with N-methyl-N-nitrosourethane inhibits lung tumors induced by urethane in transgenic mice carrying human prototype c-Ha-ras gene" Cancer Letters. 129巻. 181-190 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Mitsumori: "Proceedings of the Fourth International Conference on Harmonization" Queen's University of Belfast, 10 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Mitsumori: "Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for 6-month corcinogenicity studies" Toxicologic Pathology. 26巻(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Mitsumori: "Pulmorary fibrosis caused by MNUR inhibits lung tumorigenesis by urethane in transgenic mice carrying the human prototype c-Ha-ras gene" Cancer Letters. 122巻(印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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