2022 Fiscal Year Final Research Report
Association of drug resistance of human malignant glioma cells and DNA repair system
Project/Area Number |
20K09334
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 56010:Neurosurgery-related
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Research Institution | Fujita Health University |
Principal Investigator |
Hirose Yuichi 藤田医科大学, 医学部, 教授 (60218849)
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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)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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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 |
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.
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Free Research Field |
脳神経外科学
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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。
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