Mechanisim of acqired drug resistance by glioma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10876
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Fujita Health University
• Principal Investigator: Hirose Yuichi 藤田医科大学, 医学部, 教授 (60218849)
• Co-Investigator(Kenkyū-buntansha): 安達 一英 藤田医科大学, 医学部, 准教授 (10338056) ; 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): 2017-04-01 – 2020-03-31
• Keywords: 膠芽腫 / DNAメチル化剤 / 薬剤耐性 / DNAミスマッチ修復

Outline of Final Research Achievements

Temozolomide (TMZ) is a main therapeutic drug for malignant glioma which is representative brain tumor. induces prolonged arrest of human glioma cells in the G2/M phase and inhibition of the G2 checkpoint intensifies the effect of TMZ. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. To clarify the mechanism of TMZ resistance, we established TMZ-resistant (TR) clones by serial treatment of U87MG cells with TMZ. We evaluated TMZ-induced cell cycle arrest and the effect of various G2 checkpoint inhibitors. We observed that longer exposure (over 6 months) to TMZ enriched the proportion of TR clones that underwent only minimal G2 arrest following TMZ treatment compared to short exposure (4 months) to TMZ. Expression of MSH6 was reduced in these clones. None of the G2 checkpoint inhibitors could resensitize TR clones to TMZ. Longer drug treatment may induce resistance of cells to DNA damaging agent(s) by means of mismatch repair modification.

Free Research Field

脳神経外科学

Academic Significance and Societal Importance of the Research Achievements

DNA メチル化剤 temozolimide (TMZ)は悪性グリオーマの治療の中心になるや薬剤であるが、その耐性機構として従来からDNA修復酵素O6-methylguanine methyltransferase (MGMT)の発現が重視されてきた。しかし我々の検討では、TMZ耐性獲得の上ではDNAミスマッチ修復機構(MMR)の異常がより重要な意義を持ち、様々な薬剤で処理を行ってもTMZに対する再感受性化は認められなかった。
グリオーマ細胞のTMZ耐性は繰り返す薬剤処理に基づくMMR異常によって獲得されるため、治療早期に強力な治療を加えることが腫瘍進行の抑制に貢献するとの考察を得た。