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. © 2002 Wiley-Liss, Inc.

Tentori L., P.I. (2002). Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G2/M cell accumulation induced by temozolomide in malignant glioma cells, 40(1), 44-54 [10.1002/glia.10113].

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

TENTORI, LUCIO;TORINO, FRANCESCO;GRAZIANI, GRAZIA
2002

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. © 2002 Wiley-Liss, Inc.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14
English
Con Impact Factor ISI
Cell cycle; Drug resistance; Glioblastoma multiforme; Methylating agent; Telomerase
Tentori L., P.I. (2002). Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G2/M cell accumulation induced by temozolomide in malignant glioma cells, 40(1), 44-54 [10.1002/glia.10113].
Tentori, L; Portarena, I; Torino, F; Scerrati, M; Navarra, P; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/52883
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