Abstract | UNLABELLED: 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. PURPOSE: To evaluate the potential toxicity of Me-Lex, used as single agent or combined with PARP-1 inhibitors, in normal peripheral blood lymphocytes (PBL). METHODS: 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. RESULTS: (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. CONCLUSIONS:
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.
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Authors | Lucio Tentori, Ilaria Portarena, Patrizia Vernole, Barry Gold, Grazia Graziani |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 49
Issue 3
Pg. 217-24
(Mar 2002)
ISSN: 0344-5704 [Print] Germany |
PMID | 11935214
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Alkylating Agents
- Enzyme Inhibitors
- Mutagens
- Poly(ADP-ribose) Polymerase Inhibitors
- methyl lexitropsin
- Netropsin
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Topics |
- 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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