New insights into the synergism of nucleoside analogs with radiotherapy.
New insights into the synergism of nucleoside analogs with radiotherapy.
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关于核苷类似物与放疗协同作用的新见解。
DOI：
10.1186/1748-717x-8-223
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发表时间：
2013-09-26
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Lee MW;Parker WB;Xu B
在临床上，核苷类似物经常与放疗联合使用，因为人们早就知道，抑制DNA修复途径是许多核苷类似物协同作用的重要手段。脱氧胞苷激酶（dCK）是许多核苷类似物抗肿瘤活性所需的关键酶，最近我们对dCK的结构和功能的理解取得了进展，阐明了该激酶在化学和放射增敏中发挥的机制作用。dCK在DNA损伤反应和细胞周期机制中迄今未被认识到的作用有助于解释这些药物与放疗的协同作用。由于目前使用的大多数核苷类似物主要由dCK激活，这些发现为集中分析和调节dCK在肿瘤中的表达和活性的努力提供了新的动力。在这篇综述中，我们将简要回顾临床使用的主要核苷类似物的药理学和生物化学被dCK激活。接下来将讨论我们对辐射反应中通过翻译后修饰激活dCK的理解的最新进展，以及目前旨在增强癌细胞中dCK活性的策略。
Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells.