Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives
Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives
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DOI：
10.1016/s0300-483x(03)00294-4
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发表时间：
2003-11-15
期刊：
影响因子：
4.5
通讯作者：
Serafin, AM
中科院分区：
文献类型：
--
作者：
Böhm, L;Roos, WP;Serafin, AM
对甲基黄嘌呤类药物己酮可可碱的新性质进行了综述，这些性质是最近才出现的，可以预期其临床应用。在总结了己酮可可碱对微循环和减少肿瘤缺氧的全身性作用，以及该药在治疗血管闭塞障碍、脑缺血、感染性疾病、感染性休克和急性呼吸窘迫方面的作用后，本文重点介绍了另一种水平的药物作用，该作用是基于对各种细胞系的体外观察。己酮可可碱和相关药物咖啡因是已知的放射增敏剂，特别是在p53突变细胞中。该药物通过促进早期进入有丝分裂而废除G2阻滞并缩短G2修复的解释不再站得住脚，因为增强放射毒性需要在照射期间药物的存在，而当药物在照射后添加到G2最大值时失败。通过测量回收率和延迟培养实验进行的修复分析确实有力地表明了修复中的作用，这一点现在通过恒定电场凝胶电泳(CFGE)测量证实了己酮可可碱，以及通过使用各种修复突变体来确认己酮可可碱和咖啡因。现在出现的图像显示，咖啡因和己酮可可碱通过靶向促进G2修复的PIK激酶家族成员(ATM和ATR)来抑制同源重组。己酮可可碱诱导的辐射剂量组之间的修复抑制以对抗组间修复已成功应用于立体定向手术的模型中。己酮可可碱在肿瘤治疗中应用的另一个现实途径来自实验，该实验表明，G2中的修复事件可以通过添加细胞毒药物和最大限度地添加己酮可可碱来直接靶向G2。在这些条件下，已经观察到高达80的大量剂量增强因子，这表明有可能在临床上实现对肿瘤生长控制的显着改善。(C)2003爱思唯尔爱尔兰有限公司。保留所有权利。
The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells. The explanation that the drug abrogates the G2 block and shortens repair in G2 by promoting early entry into mitosis is not anymore tenable because enhancement of radiotoxicity requires presence of the drug during irradiation and fails when the drug is added after irradiation at the G2 maximum. Repair assays by measurement of recovery ratios and by delayed plating experiments indeed strongly suggested a role in repair which is now confirmed for Pentoxifylline by constant field gel electrophoresis (CFGE) measurements and for Pentoxifylline and for Caffeine by use of a variety of repair mutants. The picture now emerging shows that Caffeine and Pentoxifylline inhibit homologous recombination by targeting members of the PIK kinase family (ATM and ATR) which facilitate repair in G2. Pentoxifylline induced repair inhibition between irradiation dose fractions to counter interfraction repair has been successfully applied in a model for stereotactic surgery. Another realistic avenue of application of Pentoxifylline in tumour therapy comes from experiments which show that repair events in G2 can be targeted directly by addition of cytotoxic drugs and Pentoxifylline at the G2 maximum. Under these conditions massive dose enhancement factors of up to 80 have been observed suggesting that it may be possible to realise dramatic improvements to tumour growth control in the clinic. (C) 2003 Elsevier Ireland Ltd. All rights reserved.