Susceptibility to chemotherapeutic alkylating agents depends on the MGMT genotype

• Project/Area Number: 10680777
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: KYUSHU UNIVERSITY
• Principal Investigator: SAKUMI Kuihiko Med. Inst. Bioreg., Kyushu University, Research associate, 生体防御医学研究所, 助手 (50211933)
• Co-Investigator(Kenkyū-buntansha): 作見 邦彦 九州大学, 生体防御医学研究所, 助手 (50211933)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 1998: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: knockout mouse / MGMT / OィイD16ィエD1-methylguanine / mutation / dacarbazine / chemotherapeutic agent / methyltransferase / 副作用 / O^6メチルグアニン

Research Abstract

An important feature of OィイD16ィエD1-methylguanine-DNA methyltransferase (MGMT) knockout mice is an increased susceptibility to alkylating agents both in an acute toxicity and in tumorigenesis. Here we show that MGMTィイD1-/-ィエD1 mice are about 20 times sensitive to chemotherapeutic agent, dacarbazine, as compared to wild type mice, and a number of tumors occurred following exposure to a low dose of the drug. Susceptibility to another chemotherapeutic agent, ACNU, was also increased, however that to cyclophosphamide was not affected. These results show that OィイD16ィエD1-alkylguanine in DNA is a molecule that exhibits cytotoxic effect at animal level, and the repair methyltransferase counteract to the effect to protect mice. Because MGMTィイD1-/-ィエD1 mice have no distinct phenotype without alkylating agent treatment, there may be couples of individuals deficient in the enzyme activity in human population. We propose that, for the chemotherapy using either triazene type or nitrosourea type of anti cancer drugs, the amount of medicine applied should be determined not only by the body weight or body surface area but also by MGMT activity of the blood cells for each patient.

Research Products

• [Publications] Kawate, H. et al: "A defect in a single allele of the Mih1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice"Carcinogenesis. 21. 301-305 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kawate, H. et al: "Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes."Proc. Natl. Acad. Sci., USA. 95. 5116-5120 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kawate H, Itoh R, Sakumi K, Nakabeppu Y, Tsuzuki T, Ide F, Ishikawa T, Noda T, Nawata H, Sekiguchi, M.: "A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenicactions of an alkylating carcinogen in methyltransferase-deficient mice."Carcinogenesis. 21(2). 301-305 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kawate H, Sakumi K, Tsuzuki T, Nakatsuru Y, Ishikawa T, Takahashi S, Takano H, Noda T, Sekiguchi, M.: "Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes."Proc. Natl. Acad. Sci. USA. 95(9). 5116-5120 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kawate,H. et al.: "A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice"Carcinogenesis. 21. 301-305 (2000)
• [Publications] Kawate, H., Sakumi, K. 他: "Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes." Proc. Natl. Acad. Sci. USA. 95. 5116-5120 (1998)