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.

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.
AuthorsLucio Tentori, Ilaria Portarena, Patrizia Vernole, Barry Gold, Grazia Graziani
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 49 Issue 3 Pg. 217-24 (Mar 2002) ISSN: 0344-5704 [Print] Germany
PMID11935214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Alkylating Agents
  • Enzyme Inhibitors
  • Mutagens
  • Poly(ADP-ribose) Polymerase Inhibitors
  • methyl lexitropsin
  • Netropsin
  • Alkylating Agents (toxicity)
  • Apoptosis (drug effects)
  • Cell Division (drug effects)
  • Cell Survival (drug effects)
  • Enzyme Inhibitors (toxicity)
  • Flow Cytometry
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation (drug effects)
  • Lymphocytes (cytology, drug effects, immunology)
  • Mutagens (toxicity)
  • Netropsin (analogs & derivatives, toxicity)
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Reference Values
  • Tumor Cells, Cultured

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