G1 arrest induction represents a critical determinant for cisplatin cytotoxicity in G1 checkpoint-retaining human cancers
G1 arrest induction represents a critical determinant for cisplatin cytotoxicity in G1 checkpoint-retaining human cancers
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DOI：
10.1097/cad.0b013e32801429ed
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发表时间：
2007-04-01
影响因子：
2.3
通讯作者：
Un, Frank
中科院分区：
文献类型：
--
作者：
Un, Frank
顺铂已被有效地用于治疗各种人类癌症类型；然而，其细胞毒性的确切机制尚不清楚。在真核生物中，通过G的进程由一个检查点监控，该检查点执行G，在DNA损伤的情况下停止，以便在开始DNA复制之前有时间进行修复。视网膜母细胞瘤肿瘤抑制基因是哺乳动物检查点G的一个组成部分。视网膜母细胞瘤基因作为人类癌症治疗的效用已被研究。有趣的是，视网膜母细胞瘤基因治疗的细胞毒性特征与顺铂的临床靶点密切相关。这促使人们对检查点诱导的G，阻滞在顺铂细胞毒性中的潜在作用进行了调查。在这里，证据表明G，阻滞诱导是顺铂诱导裂解路径的关键步骤。首先，经顺铂治疗的人类癌细胞在死亡前经历长时间的G -阻滞。其次，在没有顺铂的情况下，通过感染表达人视网膜母细胞瘤基因的重组腺病毒触发G，阻滞足以增强致死率。第三，致死性的程度与异位表达的人视网膜母细胞瘤多肽的G(1)抑制潜能相关。第四，对顺铂耐药的人类癌细胞尽管接受顺铂治疗，但不会发生G -阻滞。上述机制可能被用于开发既保留顺铂疗效又绕过其与继发性肿瘤形成相关的致突变性的治疗方法。
Cisplatin has been used effectively to treat various human cancer types; yet, the precise mechanism underlying its cytotoxicity remains unknown. In eukaryotes, progression through G, is monitored by a checkpoint, which executes G, arrest in the event of DNA damage to allow time for repair before initiating DNA replication. The retinoblastoma tumor suppressor gene is an integral component of the mammalian G, checkpoint. The utility of the retinoblastoma gene as a therapeutic for human cancers has been investigated. Intriguingly, the cytotoxicity profile of the retinoblastoma gene therapy closely parallels the clinical targets of cisplatin. It prompted an investigation into the potential role of the checkpoint-induced G, arrest in cisplatin cytotoxicity. Here, the evidence that G, arrest induction represents a critical step in cisplatin-induced lytic path is presented. First, cisplatin-treated human cancer cells undergo a prolonged G, arrest before dying. Second, triggering G, arrest via infection with a recombinant adenovirus expressing the human retinoblastoma gene is sufficient to potentiate lethality in the absence of cisplatin. Third, the extent of the lethality induced correlates with the G(1)-arresting potential of the ectopically expressed human retinoblastoma polypeptide. Fourth, human cancer cells resistant to cisplatin do not undergo G, arrest despite cisplatin treatment. The above mechanism may be exploited to develop therapeutics that preserve the efficacy of cisplatin yet bypass its mutagenicity associated with the formation of secondary tumors.