Novel strategy to enhance temozolomide sensitivity with interference of base excision DNA repair system for malignant glioma

2016 Fiscal Year Final Research Report

• Project/Area Number: 25462277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kyorin University
• Principal Investigator: Nagane Motoo 杏林大学, 医学部, 教授 (60327468)
• Research Collaborator: SHIOKAWA Yoshiaki ; OKADA Kyoko ; SHIMIZU Saki ; SUZUKI Kaori ; McDONALD Kerrie
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: 脳腫瘍 / 神経膠腫 / PARP阻害剤 / テモゾロミド耐性

Outline of Final Research Achievements

Glioblastoma (GBM) is highly malignant and intractable to standard temozolomide (TMZ) treatment. TMZ induces cytotoxic O6-methylguanine lesion in tumor cell DNA, which is repaired by MGMT leading to TMZ resistance. TMZ preferentially induces N7-methylguanine and N3-methylalanine lesions, but they can be repaired through base excision repair system where poly (ADP-ribose) polymerase (PARP) plays a central role. Thus interference with PARP would be expected to conquer TMZ resistance. We treated human GBM cell lines with PARP inhibitors (ABT888) with or without TMZ and found that combination of TMZ plus ABT888 significantly strengthened cell death in GBM cell lines with methylated MGMT but also in those with unmethylated MGMT compared to either treatment alone. This synergistic effect was further observed in GBM cell lines derived from TMZ refractory patients as well as TMZ-resistant subclones. These results suggest the potential clinical usefulness of combining PARP inhibitors to TMZ.

Free Research Field

脳腫瘍