Apoptotic and genotoxic effects of a methyl sulfonate ester that selectively generates N3-methyladenine and poly(ADP-ribose) polymerase inhibitors in normal peripheral blood lymphocytes

• Published in: Cancer chemotherapy and pharmacology 2002-03, Vol.49 (3), p.217-224
• Main Authors: TENTORI, Lucio, PORTARENA, Ilaria, VERNOLE, Patrizia, GOLD, Barry, GRAZIANI, Grazia
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Cell Survival - drug effects; Chemotherapy; Enzyme Inhibitors - toxicity; Flow Cytometry; Humans; Jurkat Cells; Lymphocyte Activation - drug effects; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - immunology; Medical sciences; Mutagens - toxicity; Netropsin - analogs & derivatives; Netropsin - toxicity; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerase Inhibitors; Reference Values; Tumor Cells, Cultured
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-001-0409-z

Selective N3-adenine methylation represents a novel strategy for tumors with a phenotype of poor responsiveness to a number of anticancer agents currently used in the clinic. Resistance to N3-methyladenine-inducing agents, such as MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), is due to high levels of N-methylpurine glycosylase (MPG). However, tumor cells with high MPG activity can be rendered susceptible to Me-Lex using poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). PBL either resting or activated with phytohemagglutinin (PHA), obtained from healthy donors, were treated with graded concentrations of Me-Lex with or without PARP-1 inhibitor (3-aminobenzamide, AB, or NU1025, NU). MPG activity, apoptosis and sister chromatid exchanges (SCE) were evaluated. (a) Me-Lex was cytotoxic mainly in PHA-activated PBL with low MPG activity; (b) combined treatment with Me-Lex and AB induced apoptotic effects as early as 24 h after drug exposure both in non-stimulated and PHA-activated PBL. When concentrations of PARP-1 inhibitors (25 microM NU and 4 m M AB) that produced a twofold increase in Me-Lex cytotoxicity in tumor cells were compared, NU induced a less-pronounced increase in apoptosis in PBL treated with Me-Lex; (c) Me-Lex at concentrations that allowed cytogenetic analysis did not induce a significant number of SCE; (d) PARP-1 inhibitors provoked a dose-dependent increase in SCE, but 25 microM NU was devoid of genotoxic effects and did not significantly increase SCE in PBL treated with Me-Lex. Me-Lex showed preferential cytotoxicity against mitogen-activated PBL. Our results also indicated that for each PARP-1 inhibitor it is necessary to define the concentration devoid of genotoxic effects in normal cells, but still capable of enhancing the efficacy of DNA-damaging agents in tumor cells.