Purpose: To evaluate the antitumor activity of single versus split exposure of neoplastic cells to temozolomide (TZM) and poly(ADP-ribose) polymerase (PARP) inhibitor. Methods: A leukemic Jurkat cell line and freshly isolated leukemic blasts were used. Jurkat cells are resistant to O-6-methylguanine damage induced by TZM due to high levels of O-6-alkylguanine-DNA alkyltransferase and to a functional defect in the mismatch repair system. Cells were treated with 3-aminobenzamide or with NU1025 to inhibit PARP activity. TZM was added to cell cultures immediately after PARP inhibitors. The concentrations of TZM used were 62.5 CIM (corresponding to the peak plasma concentration in patients) or 125 muM. Treatment design: Cells were treated with 125 muM TZM plus PARP inhibitors (single exposure), or twice with 62.5 muM TZM plus PARP inhibitors with an interval of 24 h between treatments (split exposure). Tumor cell growth, clastogenicity and base excision repair gene transcripts or enzymatic activity were evaluated. Results: The split exposure of Jurkat cells to TZM induced more pronounced and persistent growth inhibition and comparable chromosome damage in comparison with the single exposure. In addition, PARP inhibitors potentiated the cytotoxic effects induced by repeated treatment with TZM in fresh leukemic blasts. A marked decrease in X-ray repair cross-complementing I transcript and methylpurine glycosylase (MPG) transcript was detected in Jurkat cells subjected to the split exposure. In this case, a significant reduction in the corresponding enzymatic activity was also observed. Conclusions: Cytotoxicity induced by TZM and PARP inhibitors can be improved by a fractionated modality of drug treatment. The reduction in MPG transcript and function would presumably contribute to an increase in cell susceptibility to DNA damage induced by the methylating agent and PARP inhibitors.

Tentori, L., Portarena, I., Vernole, P., De Fabritiis, P., Madaio, R., Balduzzi, A., et al. (2001). Effects of single or split exposure of leukemic cells to temozolomide, combined with poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and base excision repair components. CANCER CHEMOTHERAPY AND PHARMACOLOGY, 47(4), 361-369 [10.1007/s002800000248].

Effects of single or split exposure of leukemic cells to temozolomide, combined with poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and base excision repair components

TENTORI, LUCIO;VERNOLE, PATRIZIA;De Fabritiis P.;BONMASSAR, ENZO;GRAZIANI, GRAZIA
2001-01-01

Abstract

Purpose: To evaluate the antitumor activity of single versus split exposure of neoplastic cells to temozolomide (TZM) and poly(ADP-ribose) polymerase (PARP) inhibitor. Methods: A leukemic Jurkat cell line and freshly isolated leukemic blasts were used. Jurkat cells are resistant to O-6-methylguanine damage induced by TZM due to high levels of O-6-alkylguanine-DNA alkyltransferase and to a functional defect in the mismatch repair system. Cells were treated with 3-aminobenzamide or with NU1025 to inhibit PARP activity. TZM was added to cell cultures immediately after PARP inhibitors. The concentrations of TZM used were 62.5 CIM (corresponding to the peak plasma concentration in patients) or 125 muM. Treatment design: Cells were treated with 125 muM TZM plus PARP inhibitors (single exposure), or twice with 62.5 muM TZM plus PARP inhibitors with an interval of 24 h between treatments (split exposure). Tumor cell growth, clastogenicity and base excision repair gene transcripts or enzymatic activity were evaluated. Results: The split exposure of Jurkat cells to TZM induced more pronounced and persistent growth inhibition and comparable chromosome damage in comparison with the single exposure. In addition, PARP inhibitors potentiated the cytotoxic effects induced by repeated treatment with TZM in fresh leukemic blasts. A marked decrease in X-ray repair cross-complementing I transcript and methylpurine glycosylase (MPG) transcript was detected in Jurkat cells subjected to the split exposure. In this case, a significant reduction in the corresponding enzymatic activity was also observed. Conclusions: Cytotoxicity induced by TZM and PARP inhibitors can be improved by a fractionated modality of drug treatment. The reduction in MPG transcript and function would presumably contribute to an increase in cell susceptibility to DNA damage induced by the methylating agent and PARP inhibitors.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14
English
Con Impact Factor ISI
3 aminobenzamide; 6 o alkylguanine DNA alkyltransferase; 6 o methylguanine; 8 hydroxy 2 methyl 4(3h) quinazolinone; clastogen; cytotoxic agent; DNA glycosyltransferase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; temozolomide; unclassified drug; alkylating agent; dacarbazine; DNA; drug derivative; enzyme inhibitor; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; article; chromosome aberration; controlled study; DNA damage; drug efficacy; drug mechanism; excision repair; growth inhibition; human; human cell; leukemia cell; priority journal; tumor growth; biosynthesis; cell division; cell survival; DNA repair; down regulation; drug antagonism; drug effect; flow cytometry; leukemia cell line; Northern blotting; Antineoplastic Agents, Alkylating; Blotting, Northern; Cell Division; Cell Survival; Chromosome Aberrations; Dacarbazine; DNA; DNA Repair; Down-Regulation; Enzyme Inhibitors; Flow Cytometry; Humans; Jurkat Cells; Poly(ADP-ribose) Polymerases
Tentori, L., Portarena, I., Vernole, P., De Fabritiis, P., Madaio, R., Balduzzi, A., et al. (2001). Effects of single or split exposure of leukemic cells to temozolomide, combined with poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and base excision repair components. CANCER CHEMOTHERAPY AND PHARMACOLOGY, 47(4), 361-369 [10.1007/s002800000248].
Tentori, L; Portarena, I; Vernole, P; De Fabritiis, P; Madaio, R; Balduzzi, A; Roy, R; Bonmassar, E; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/52882
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