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
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
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DOI：
10.1007/s002800000248
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发表时间：
2001-04-01
影响因子：
3
通讯作者：
Graziani, G
中科院分区：
文献类型：
--
作者：
Tentori, L;Portarena, I;Graziani, G
目的：评估肿瘤细胞单次暴露于替莫唑胺 (TZM) 和聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂的抗肿瘤活性。方法：使用白血病 Jurkat 细胞系和新鲜分离的白血病母细胞。由于高水平的 O-6-烷基鸟嘌呤-DNA 烷基转移酶和错配修复系统的功能缺陷，Jurkat 细胞对 TZM 诱导的 O-6-甲基鸟嘌呤损伤具有抵抗力。用 3-氨基苯甲酰胺或 NU1025 处理细胞以抑制 PARP 活性。在 PARP 抑制剂之后立即将 TZM 添加到细胞培养物中。使用的 TZM 浓度为 62.5 CIM（对应于患者的血浆峰值浓度）或 125 muM。处理设计：用125μM TZM加PARP抑制剂处理细胞（单次暴露），或用62.5μM TZM加PARP抑制剂处理细胞两次，处理之间间隔24小时（分次暴露）。评估肿瘤细胞生长、染色体断裂性和碱基切除修复基因转录物或酶活性。结果：与单次暴露相比，Jurkat 细胞分次暴露于 TZM 会引起更明显和持久的生长抑制以及相当的染色体损伤。此外，PARP 抑制剂增强了在新鲜白血病细胞中用 TZM 重复治疗诱导的细胞毒性作用。在接受分割曝光的 Jurkat 细胞中，检测到 X 射线修复交叉互补 I 转录本和甲基嘌呤糖基化酶 (MPG) 转录本显着减少。在这种情况下，还观察到相应的酶活性显着降低。结论：TZM 和 PARP 抑制剂诱导的细胞毒性可以通过分次药物治疗方式得到改善。 MPG 转录物和功能的减少可能会导致细胞对甲基化剂和 PARP 抑制剂诱导的 DNA 损伤的敏感性增加。
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.