Treatment with temozolomide and poly(ADP-ribose) polymerase inhibitors induces early apoptosis and increases base excision repair gene transcripts in leukemic cells resistant to triazene compounds
Treatment with temozolomide and poly(ADP-ribose) polymerase inhibitors induces early apoptosis and increases base excision repair gene transcripts in leukemic cells resistant to triazene compounds
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DOI：
10.1038/sj.leu.2401423
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发表时间：
1999-06-01
期刊：
影响因子：
11.4
通讯作者：
Graziani, G
中科院分区：
文献类型：
--
作者：
Tentori, L;Turriziani, M;Graziani, G
甲基化三氮烯显示出明显的抗白血病作用，可能是通过产生多种DNA加合物。由于错配修复系统（MRS）的缺陷，对o -6-甲基鸟嘌呤耐受的细胞可能通过抑制n -甲基嘌呤修复而对其他甲基加合物敏感，这需要碱基切除修复（BER）和聚（adp核糖）聚合酶（PADPRP）。因此，使用替莫唑胺（TZM）和PADPRP抑制剂治疗耐甲基化三氮杂烯的mrs缺陷Jurkat白血病细胞。PADPRP或参与BER系统的分子[3-甲基嘌呤- dna糖基化酶（MPG）和x射线修复交叉互补1 (XRCC1)]的表达已被探索。与PADPRP抑制剂相关的TZM的细胞毒性作用在治疗后不久就很明显，这表明细胞分裂的完成并不需要药物组合的致命作用。单独使用TZM或联合使用PADPRP抑制剂治疗后，发现PADPRP或MPG转录本增加。XRCC1转录本仅在联合用药的情况下被正调节。这可能表明，在PADPRP抑制剂存在的情况下，DNA损伤的持续性触发XRCC1转录。我们的研究结果表明，TZM和PADPRP抑制剂的关联可能对对甲基化剂无反应的mrs缺陷恶性肿瘤有益。
Methylating triazenes have shown marked antileukemic effects, possibly through generation of a variety of DNA adducts. Cells tolerant to O-6-methylguanine due to a defect in the mismatch repair system (MRS), might become sensitive to other methyl adducts, by inhibiting the N-methylpurine repair, which requires base excision repair (BER) and poly(ADP-ribose) polymerase (PADPRP). Therefore, MRS-deficient Jurkat leukemic cells resistant to methylating triazenes, have been treated with temozolomide (TZM) and PADPRP inhibitors. Expression of PADPRP or molecules involved in the BER system [3-methylpurine-DNA glycosylase (MPG) and X-ray repair cross-complementing 1 (XRCC1)], have been explored. Cytotoxic effects of TZM associated with PADPRP inhibitors are evident shortly after treatment, suggesting that completion of cell division is not required for the lethal effect of the drug combination. Increase of PADPRP or MPG transcripts was found after treatment with TZM alone or combined with PADPRP inhibitor. XRCC1 transcript was positively modulated only in the case of drug combination. This could suggest that in the presence of PADPRP inhibitor, persistence of DNA damage triggers XRCC1 transcription. Our results suggest that association of TZM and PADPRP inhibitors might be of benefit for MRS-deficient malignancies unresponsive to the methylating agent.