Poly(ADP‐ribose) polymerase inhibitor increases growth inhibition and reduces G2/M cell accumulation induced by temozolomide in malignant glioma cells

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Abstract
Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high‐grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)‐mediated processing of O6‐methylguanine:T mispairs. N3‐methyladenine and N7‐methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP‐ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N‐methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53–wild‐type or p53‐mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O6‐methylguanine damage and show low sensitivity to TZM. In O6‐alkylguanine‐DNA alkyltransferase (OGAT)‐deficient and MR‐proficient tumor cells bearing wild‐type p53, the drug combination markedly reduced cell accumulation in the G2/M phase of cell cycle and induction of the G2 checkpoint regulator Chk1 kinase. In short‐term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT‐proficient tumors. Thus, a pharmacological strategy based on the interruption of N‐methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM. GLIA 40:44–54, 2002.