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2005 Fiscal Year Final Research Report Summary

Nobel therapeutic strategy based on deficient expression of DNA repair gene in gastrointestinal cancers.

Research Project

Project/Area Number 15390400
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionSaga University (2004-2005)
佐賀医科大学 (2003)

Principal Investigator

MIYAZAKI Kohji  Saga University, Faculty of Medicine, Professor, 医学部, 教授 (30159173)

Co-Investigator(Kenkyū-buntansha) KITAJIMA Yoshihiko  Saga University, Faculty of Medicine, Lecturer, 医学部, 講師 (30234256)
Project Period (FY) 2003 – 2005
KeywordsMGMT / hMLH1 / DNA repair gene / Alkylating agents / Gastrointestinal cancer / Selective chemotherapy / CHFR / DPD
Research Abstract

Expression of O^6 methylguanine DNA methyltransferase (MGMT) and mismatch repair gene hMLH1 was frequently lost in gastrointestinal cancer including biliary tract, hepatocellular, gastric and colorectal cancers. We previously reported significant correlation between deficient expression of MGMT, hMLH1 gene and poor outcome in biliary tract, hepatocellular and gastric cancer patients. MGMT is known as repair enzyme against alkylating modifications of cellular DNA. Recent reports using MGMT/hMLH1 knockout mice demonstrated that mice with MGMT(-) /hMLH1(+) was highly sensitive to alkylating agent MNU, leading to death by severe myelosuppression. We hypothesized that drug sensitivity to alkylating anticancer drug might depend on expression status of MGMT and hMLH1 in cancer cells. In this research project, we attempted to build a novel therapeutic strategy using alkylating agents, in which the drug sensitivity is predictable by MGMT/hMLH1 gene expression before chemotherapeutic treatment.
1 … More (2003) Using 6 biliary tract acncer cell lines, we correlated expression pattern of MGMT/hMLH1 gene with drug sensitivity to alkylating agent MNU. As a result, 2 cell lines with MGMT(-)/hMLH1(+) was the most highly sensitive to MNU, compared with resultant cells with MGMT(+)/hMLH1(+) or MGMT(-)/hMLH1(-). This association was also found in xenograft tumor on nude mice. These results suggested that expression status of MGMT/hMLH1 is a marker for predicting drug sensitivity to alkylating agents. Furthermore, we found MGMT expression was suppressed under cisplatin with low dose concentration. This result indicated a novel biochemical modulation therapy using alkylating agents, where MGMT positive cancer cellscould be altered to MGMT deficient type by cisplatin treatment.
2 (2004) It was recently reported that loss of MGMT and hMLH1 expressions in cancer were mainly caused by epigenetic gene methylation. Thus we analyzed methylation status of MGMT, hMLH1 in biliary tract cancer tissues. We demonstrated a significant correlation between MGMT methylation and reduced expression of MGMT protein. This result suggested MGMT methylation in cancer cells, which leading to the reduced protein expression, is molecular marker predicting drug sensitivity to alkylating agents.
3 (2005) We found significant correlation between hMLH1 (-) status and high sensitivity to topoisomerase 1 inhibitor CPT-11 in biliary trac cancer cells. We confirmed the association by hMLH1 siRNA transfection to cancer cells with hMLH1 (+). Besides, we found DPD deficient cell line among 6 biliary tract cancer cells. We elucidated epigenetic modification of DPD gene occured in this cell line. DPD is known as an important enzyme determinating sensitivity to 5-FU. Thus we indicated deficient DPD expression in gastrointestinal cancer might be molecular marker predicting drug sensitivity to 5-FU. In gastric cancer cell lines and tissues, we observed significant correlation of CHFR gene methylation with high sensitivity to mictotubule inhibitor, Taxan. These results contributed to enriching molecular marker for selecting various anticancer drugs. We are willing to develop this research project and apply to our protocol for clinical cancer treatment. Less

  • Research Products

    (11 results)

All 2005 2004 Other

All Journal Article (11 results)

  • [Journal Article] Cisplatin represses transcriptional activity from the minimal promoter of MGMT gene and increases sensitivity of human gallblandder cancer cells.2005

    • Author(s)
      K.Sato et al.
    • Journal Title

      Oncology Reports 13

      Pages: 899-906

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Deficient MGMT and proficient hMLH1 expression renders gallbladder carcinoma cells sensitive to alkylating agents through G2-M cell cycle arrest.2005

    • Author(s)
      K.Sato et al.
    • Journal Title

      International Journal of Oncology 26

      Pages: 1653-1661

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The effect of MGMT and hMLH1 status on the sensitivity to alkylating agent ACNU in gallbladder carcinoma cells.2005

    • Author(s)
      K.Sato et al.
    • Journal Title

      Anticancer Research 25

      Pages: 4021-4025

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Tumor progression through epigenetic gene silencing of MGMT in human biliary tract cancers.2005

    • Author(s)
      Y Koga et al.
    • Journal Title

      Annals of Surgical Oncology 12

      Pages: 354-363

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Deficient MGMT and proficient hMLH1 expression renders gallbladder carcinoma cells sensitive to alkylating agents through G2-M cell cycle arrest.2004

    • Author(s)
      K.Sato et al.
    • Journal Title

      International Journal of Oncology 26

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Deficient expression of DPD gene is caused by epigenetic modification in biliary tract cancer cells, and induces high sensitivity to 5-FU treatment.

    • Author(s)
      K Sato et al.
    • Journal Title

      International Journal of Oncology (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The significance of aberrant CHFR methylation for clinical response to microtubule inhibitors in gastric cancer

    • Author(s)
      Y Koga et al.
    • Journal Title

      Journal of Gastroenterology (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cisplatin represses transcriptional activity from the minimal promoter of MGMT gene and increases sensitivity of human gallbladder cancer cells.

    • Author(s)
      K Sato et al.
    • Journal Title

      Oncology Reports 13

      Pages: 899-906

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The effect of MGMT and hMLH1 status on the sensitivity to alkylating agent ACNU in gallbladder carcinoma cells.

    • Author(s)
      K Sato et al.
    • Journal Title

      Anticancer Research 25

      Pages: 4021-4025

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Deficient expression of DPD gene is caused by epigenetic modification in biliary tract cancer cells, and induces high sensitivity to 5-FU

    • Author(s)
      K Sato et al.
    • Journal Title

      International Journal of Oncology (In press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] he significance of aberrant CHFR methylation for clinical response to microtubule inhibitors in gastric cancer

    • Author(s)
      Y Koga et al.
    • Journal Title

      Journal of Gastroenterology (In press)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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