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Identification of DNA adducts in animals and breast cancer patients treated with tamoxifen

Research Project

Project/Area Number 10671119
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionThe University of Tokushima

Principal Investigator

UMEMOTO Atsushi  Second Department of Surgery, School of Medicine, The University of Tokushima, MD, Ph.D. Assistant Professor, 医学部・附属病院, 講師 (60185072)

Co-Investigator(Kenkyū-buntansha) SUWA Masato  Pharmaceuticals Group, Nippon Kayaku Co., Ltd., Chief Investigator, 研究員
KOMAKI Kansei  Second Department of Surgery, School of Medicine, The University of Tokushima, MD, Ph.D. Assistant Professor, 医学部・附属病院, 講師 (60215382)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥3,500,000 (Direct Cost: ¥3,500,000)
Keywordstamoxifen / α-(NィイD12ィエD1-deoxyguanosinyl)tamoxifen N-oxide / DNA adduct / ィイD132ィエD1P-postlabeling / endometrial cancer / ^<32>P-ポストラベル法 / ヒト白血球 / 発癌 / ^<32>p postlabeling
Research Abstract

It is known that a long term treatment of tamoxifen for the breast cancer patients increases the incidence of endometrial cancer. The cause of this is assumed to be formation of DNA adducts by tamoxifen. In last year, we synthesized α-acetoxytamoxifen and α-acetoxytamoxifen N-oxide as activated forms, and obtained DNA adducts by reacting them with DNA and 2'-deoxyguanosine. These were identified as each four stereoisomers of α-(NィイD12ィエD1-deoxyguanosinyl)tamoxifen and α-(NィイD12ィエD1-deoxyguanosinyl) tamoxifen N-oxide by mass spectroscopy and nuclear magnetic resonance spectroscopy. In this year, we analyzed the liver samples of rats and mice treated with tamoxifen by ィイD132ィエD1P-postlabeling and m)LC using the above authentic adducts, and succeeded to detect these two types of tamoxifen-DNA adducts. In both animals, trans form of α-(NィイD12ィエD1-deoxyguanosinyl)tamoxifen was a principal DNA adduct that accounted for about 50% of the total DNA adduct level. In the mouse liver, trans form of α-(NィイD12ィエD1-deoxyguanosinyl)tamoxifen N-oxide was accounted for 7%, while in the rats it was for only 0.3%, This may be due to the higher activity of flavin-containing monooxygenase that catalyze N-oxidation of tamoxifen in the mice than rats. The DNA adducts of the patient's leucocytes was then analyzed. Trans-α-(NィイD12ィエD1-deoxyguanosinyl)tamoxifen was detected in the leucocyte DNA from the three patients among fifty breast cancer patients treated with tamoxifen. We are collecting endometrial DNA samples from the breast cancer patients treated with tamoxifen.

Report

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

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Unemoto,A., Komaki,他5名: "Identification of Tamoxifen-DNA adducts in white blood cells from breast patients"Breast Cancer Res Treat.. 50. 331 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Unemoto,A., Komaki,他9名: "Ansetti Revindernath and Shinya Shibutani,Temoxifen-DNA adducts formed by -acetoxytamoxifen N-oxide"Chem.Res.Toxicol. 12(11). 1083-1089 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Unemoto,A., Komaki,他5名: "17th International Cancer Congress"Bevilacqua(ed.)Monduzzi Editore,Bologna Italy. 1673 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Umemoto, A., Shibutani, S., Komaki, K., Suwa, M., Lin, C., Mimura, S. and Monden, Y.: "Identification of Tamoxifen-DNA adducts in white blood cells from breast cancer patients."Breast Cancer Res. Treat.. 50. 331 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Umemoto, A., Shibutani, S., Suwa, M., Komaki, K., Lin, C., Mimura, S. and Monden, Y.: "Tamoxifen-DNA adducts in white blood cells obtained from breast cancer patients."In Marcos Moraes, Ricardo Brentani and Ruy Bevilacqua (ed.) 17th International Cancer Congress. Monduzzi Editore, Bologna Italy. 835-839 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Atsushi Umemoto, Yasumasa Monden, Kansei Komaki, Masato Suwa, Yoshikazu Kanno, Masanobu Suzuki, Chun-Xing Lin, Yuji Ueyama, Md. Abdul Momen: "Anisetti Ravindernath and Shinya Shibutani Tamoxifen-DNA adducts formed by α-acetoxytamoxifen N-oxide."Chem. Res. Toxicol.. 12(11). 1083-1089 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Umemoto,A.,Komaki,他5名: "Identification of Tamoxifen-DNA adducts in white blood cells from breast cancer patients."Breast Cancer Res.Treat.. 50. 331 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Umemoto,A.,Komaki,他9名: "Anisetti Ravindernath and Shinya Shibutani,Tamoxifen-DNA adducts formed by -acetoxytamoxifen N-oxide"Chem.Res.Toxicol. 12(11). 1083-1089 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Umemoto,A.,Komaki,他5名: "17th International Cancer Congress."Bevilacqua(ed.)Monduzzi Editore,Bologna Italy. 1673 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Umemoto,A.Shibutani,S.Suwa,M.Komaki,K.Lin,C.Mimura,S.and Monden,Y.: "Tamoxifen-DNA adducts in white blood cells obtained from breast cancer patients" In Maoraes,Ricardo Brentani and Ruy Bevilacque(ed.)17th international Cancer COngress.Monduzzi Editore,Bologna Italy. 835-839 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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