Elucidation of temozolomide resistance mechanism which is not involved in MGMT in malignant glioma

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591617
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Kagoshima University
• Principal Investigator: YASHIRO Kazutaka 鹿児島大学, 医歯学総合研究科, 客員研究員 (20264418)
• Co-Investigator(Kenkyū-buntansha): ARITA Kazunori 鹿児島大学, 医歯学総合研究科, 教授 (90212646) ; HIRANO Hirofumi 鹿児島大学, 医学部・歯学部附属病院, 講師 (00264416) ; FURUKAWA Tatsuhiko 鹿児島大学, 医歯学総合研究科, 教授 (40219100)
• Project Period (FY): 2010 – 2012
• Keywords: 膠芽腫 / temozolomide / 耐性 / MLH1 / ABC トランスポーター

Research Abstract

Treatment with the alkylating agent temozolomide (TMZ) has resulted in benefits for patients with glioblastoma (GBM). Nevertheless, almost all GBMs recur and lead to death of the patient. It is therefore critically important to determine the mechanisms of acquisition of TMZ resistance. Methods:To analyze the mechanism of TMZ-resistance of gliomas, we isolated three TMZ-resistant human glioma U251 cell lines. We examined mRNA expression of mismatch repair (MMR) componentsof the TMZ-resistant cells and evaluated the expression of MutL homolog 1 (MLH1) , with immunohistochemically in GBM specimens obtained from patients who had undergone total or subtotal tumor removal and who suffered from recurrence during administration of TMZ. Results: We found that MLH1 mRNA and protein expression was decreased in all three independent TMZ-resistant cell lines compared to the parental cells and that knock-down of MLH1 expression decreased the TMZ sensitivity of the parent cells. Moreover MLH1 expression was reduced in the recurrent human GBMs during administration of TMZ compared to the level in the initial tumor. Conclusions:We conclude that U251 glioma cells acquire resistance to TMZ by reducing the expression of MLH1 and that a decrease in MLH1 is associated with the recurrence of GBM.