文章：

靶向检查点激酶：化学致敏与化学保护

Targeting the checkpoint kinases: chemosensitization versus chemoprotection

原文发布日期：2004-03-01

DOI: 10.1038/nrc1296

类型: Review Article

开放获取: 否

要点：

1. DNA-damaging agents are among the most effective anticancer agents in clinical use; however, they have significant limitations. Many patients with cancer either do not respond, or develop resistance to them, they are also toxic, and have only a limited therapeutic window.
2. The DNA-damage-response network regulates not only cell-cycle checkpoints, but also DNA repair, genome maintenance, senescence and apoptosis. Modulation of the DNA-damage response, depending on where in the network this modulation occurs, could have different consequences including chemosensitization and chemoprotection.
3. CHK1 and CHK2 were originally discovered as checkpoint kinases. However, further studies have indicated that they are actually DNA-damage-response kinases, regulating more than just cell-cycle checkpoints.
4. CHK1 regulates numerous checkpoint pathways, including S-phase and G2–M checkpoints. Other potential CHK1 functions include replication, chromatin remodelling and DNA repair. CHK1 inhibition is expected to sensitize cells to a broad spectrum of DNA-damaging agents.
5. CHK2 might have a redundant and supportive role in checkpoints, but its role in ionizing-radiation-induced apoptosis is more prominent. However, its role in other DNA-damage-induced apoptosis mechanisms is less well established. CHK2 inhibition is expected to protect normal cells from the side effects of ionizing radiation, but its role in chemoprotection still needs to be clarified.

要点翻译：

1. DNA损伤药物是临床应用中最为有效的抗癌药物之一，但其存在显著局限性。许多癌症患者对该类药物无应答或产生耐药性，同时它们还具有毒性，治疗窗口狭窄。
2. DNA损伤应答网络不仅调控细胞周期检查点，还参与DNA修复、基因组稳定性维持、细胞衰老及凋亡过程。对该网络的调控可能产生不同后果（包括化疗增敏与化疗保护），具体效应取决于干预位点。
3. CHK1与CHK2最初作为检查点激酶被发现，但后续研究表明它们实为DNA损伤应答激酶，其功能远不止于细胞周期检查点调控。
4. CHK1调控多种检查点通路（包括S期和G2-M期检查点），其他潜在功能涉及DNA复制、染色质重塑及DNA修复。抑制CHK1预期可增强细胞对多种DNA损伤药物的敏感性。
5. CHK2在检查点通路中可能起冗余辅助作用，但在电离辐射诱导的凋亡过程中作用更为突出。不过，其在其他DNA损伤诱导凋亡机制中的作用尚不明确。抑制CHK2有望保护正常细胞免受电离辐射副作用，但其在化疗保护中的作用仍需进一步阐明。

英文摘要：

An important part of the cellular response to DNA damage is checkpoint activation — checkpoint kinases CHK1 and CHK2 phosphorylate key proteins to elicit cell-cycle blocks. Inhibiting these kinases was believed to sensitize tumour cells to cancer treatments that damage DNA, because in the absence of checkpoints and efficient DNA repair, the response would switch to cell death or senescence. Recent discoveries have, however, highlighted different and expanded roles for CHK1 and CHK2, so should the therapeutic hypothesis that is concerned with targeting so-called checkpoint kinases be modified?

摘要翻译： 

细胞对DNA损伤反应的一个重要组成部分是检查点的激活——检查点激酶CHK1和CHK2通过磷酸化关键蛋白来引发细胞周期阻滞。抑制这些激酶曾被认为是使肿瘤细胞对损伤DNA的癌症治疗敏感的方法，因为在缺乏检查点和高效DNA修复的情况下，反应会转向细胞死亡或衰老。然而，最近的发现突显了CHK1和CHK2具有不同且更广泛的作用，那么针对所谓检查点激酶的治疗假设是否应该被修正？

原文链接：

Targeting the checkpoint kinases: chemosensitization versus chemoprotection