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.
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.
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甲基磺酸酯在正常外周血淋巴细胞中选择性产生 N3-甲基腺嘌呤和聚（ADP-核糖）聚合酶抑制剂的细胞凋亡和基因毒性作用。
DOI：
10.1007/s00280-001-0409-z
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Graziani,Grazia
中科院分区：
文献类型：
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作者：
Tentori,Lucio;Portarena,Ilaria;Vernole,Patrizia;Gold,Barry;Graziani,Grazia
选择性 N3-腺嘌呤甲基化代表了一种针对对目前临床上使用的多种抗癌药物反应性较差的表型肿瘤的新策略。对 N3-甲基腺嘌呤诱导剂（如 MeOSO2(CH2)2-lexitropsin (Me-Lex)）的耐药性是由于高水平的 N-甲基嘌呤糖基化酶 (MPG) 造成的。然而，使用聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂可以使具有高 MPG 活性的肿瘤细胞对 Me-Lex 敏感。 目的：评估 Me-Lex 单药使用或与 PARP-1 抑制剂联用对正常外周血淋巴细胞（PBL）的潜在毒性。 Me-Lex 含或不含 PARP-1 抑制剂（3-氨基苯甲酰胺，AB 或 NU1025，NU）。评估MPG活性、细胞凋亡和姐妹染色单体交换（SCE）。结果：（a）Me-Lex主要在MPG活性低的PHA激活的PBL中具有细胞毒性； (b) 在非刺激和 PHA 激活的 PBL 中，Me-Lex 和 AB 联合治疗最早在药物暴露后 24 小时就诱导了细胞凋亡效应。当比较使肿瘤细胞中 Me-Lex 细胞毒性增加两倍的 PARP-1 抑制剂（25 µMNU 和 4 mMAB）浓度时，NU 诱导经 Me-Lex 处理的 PBL 细胞凋亡增加，但不太明显； (c) 允许进行细胞遗传学分析的浓度的 Me-Lex 不会诱导大量的 SCE； (d) PARP-1 抑制剂引起 SCE 的剂量依赖性增加，但 25 µMNU 没有基因毒性作用，并且不会显着增加经 Me-Lex 处理的 PBL 中的 SCE。结论：Me-Lex 对丝裂原激活的 PBL 表现出优先的细胞毒性。我们的结果还表明，对于每种 PARP-1 抑制剂，有必要确定在正常细胞中不产生基因毒性作用，但仍能够增强 DNA 损伤剂在肿瘤细胞中的功效的浓度。
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 MeOSO2(CH2)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 µMNU and 4 mMAB) 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 µMNU 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.