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Association of drug resistance of human malignant glioma cells and DNA repair system

Research Project

Project/Area Number 20K09334
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionFujita Health University

Principal Investigator

Hirose Yuichi  藤田医科大学, 医学部, 教授 (60218849)

Co-Investigator(Kenkyū-buntansha) 中江 俊介  藤田医科大学, 医学部, 講師 (20622971)
佐々木 光  慶應義塾大学, 医学部(信濃町), 講師 (70245512)
大場 茂生  藤田医科大学, 医学部, 准教授 (80338061)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords悪性神経膠腫 / 薬剤耐性 / DNAミスマッチ修復 / G2チェックポイント / 膠芽腫 / DNAメチル化剤 / ミスマッチ修復 / DNA修復機構 / temozolomide
Outline of Research at the Start

悪性神経膠腫細胞が化学療法剤に対して耐性を獲得するためにはDNA修復能の亢進が必要であると考えられるが、DNA修復機構やこれと細胞内応答は腫瘍細胞が生存する上で重要と考えられ、本研究は神経膠腫に対する化学療法の増感法の開発につながる知見を供給し得ると考える。
また、DNAアルキル化剤の長期反復投与により感受性のある細胞にも薬剤耐性が獲得されうるために投与スケジュールの適切化を検討する契機になるなど、今後の新治療法開発に向けて有意義な情報を提供しうるものと考えられる。また、MMR障害はゲノムの不安定性を強くするため、新たな治療標的とできる可能性も考えられる。

Outline of Final Research Achievements

To elucidate the mechanism of drug resistance in malignant glioma, we isolated multiple drug-resistant cell lines by repeatedly treating the U87MG cell line with low concentrations of the DNA alkylating agent temozolomide (TMZ). None of the resistant strains showed expression of the DNA repair enzyme O6-methylguanine methyltransferase, suggesting that other mechanisms are involved in acquired resistance. The characteristics of the resistant strains were roughly divided into two groups. In one group, although the formation of DNA double-strand breaks occurred, it was confirmed that subsequent DNA homologous recombination repair was enhanced and, thus, cell death was suppressed. On the other hand, a group in which the toxicity of TMZ was not exhibited due to the dysfunction of DNA mismatch repair mechanism was established after longer exposure to TMZ, and showed very strong tolerance against TMZ.

Academic Significance and Societal Importance of the Research Achievements

化学療法剤に対する細胞内での生物学的応答を解明することは脳腫瘍学の発展の上で重要な意義があるが、特にDNA修復機構 (MMR)と細胞生存維持機構の関連を解明することは腫瘍の治療耐性獲得機序の解明につながり、新たな化学療法プロトコールの開発や将来の新規薬物療法の開発のための基盤形成になり得る。特に投与回数についての科学的根拠がないTMZ化学療法において、長期反復投与により感受性のある細胞にも薬剤耐性が獲得されうるために投与スケジュールの適切化を検討する必要があること、および新規薬剤のDNAアルキル化剤との併用療法は腫瘍再発の前に試みる必要性があることを示すものである。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (5 results)

All 2023 2021 2020

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells2021

    • Author(s)
      Ohba Shigeo、Yamashiro Kei、Hirose Yuichi
    • Journal Title

      Cancers

      Volume: 13 Issue: 11 Pages: 2570-2570

    • DOI

      10.3390/cancers13112570

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of preoperative seizures with tumor metabolites quantified by magnetic resonance spectroscopy in gliomas2021

    • Author(s)
      Nakae Shunsuke、Kumon Masanobu、Murayama Kazuhiro、Ohba Shigeo、Sasaki Hikaru、Inamasu Joji、Kuwahara Kiyonori、Yamada Seiji、Abe Masato、Hirose Yuichi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 7927-7927

    • DOI

      10.1038/s41598-021-86487-6

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Correlation between IDH, ATRX, and TERT promoter mutations in glioma2020

    • Author(s)
      Ohba Shigeo、Kuwahara Kiyonori、Yamada Seiji、Abe Masato、Hirose Yuichi
    • Journal Title

      Brain Tumor Pathology

      Volume: 37 Issue: 2 Pages: 33-40

    • DOI

      10.1007/s10014-020-00360-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Human Glioma Cells Acquire Temozolomide Resistance After Repeated Drug Exposure Via DNA Mismatch Repair Dysfunction.2020

    • Author(s)
      Yamashiro K, Nakao K, Ohba S, Hirose Y.
    • Journal Title

      Anticancer Research

      Volume: 40 Issue: 3 Pages: 1315-1323

    • DOI

      10.21873/anticanres.14073

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] TARGETING ASPARAGINE METABOLISM FOR TREATMENT OF PROGRESSING MALIGNANT GLIOMA.2023

    • Author(s)
      Yuichi Hirose, Shigeo Ohba, Kei Yamashiro, Kazutaka Nakao, Takao Teranishi
    • Organizer
      The 23rd International Conference on Brain Tumor Research and Therapy
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2024-01-30  

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