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Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The acquisition of resistance to TMZ and the heterogeneity of the tumor are considered to be associated with poor prognosis. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 were obtained and analyzed. A clone showed high homologous recombination (HR), and inhibition of HR resensitized the clone to TMZ. MMR system was suppressed in the other clones. Inhibition of BER by PARP inhibitor resensitized them to TMZ. PARP inhibitor enhanced the TMZ-induced cytotoxicity in glioma cells with high expression of MGMT. Dianhydrodulcitol, alkylating agent, suppressed the proliferation in U251 and even U251-derived resistant clones. These effects were shown in U87MG-dereived resistant clones and MGMT-proficient cell lines. Moreover, inhibition of HR enhanced the cytotoxicity of dianhydrodulcitol. To select the appropriate treatment according to the mechanisms of resistance to TMZ can overcome the resistance in glioma cells.

DRES-03. PARP INHIBITOR, INHIBITION OF HOMOLOGOUS RECOMBINATION, OR DIANHYDRODULCITOL CAN OVERCOME TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS