文章：

烷基化剂引起的DNA损伤的平衡修复和耐受性

Balancing repair and tolerance of DNA damage caused by alkylating agents

原文发布日期：2012-01-12

DOI: 10.1038/nrc3185

类型: Review Article

开放获取: 否

要点：

1. Chemotherapeutic alkylating agents induce a range of cytotoxic and mutagenic adducts onto DNA.
2. Alkylating agent-induced damage to DNA is sensed and repaired by different cellular mechanisms, including direct repair by the AlkB homologue (ALKBH) family and O⁶-methylguanine-DNA methyltransferase (MGMT) proteins or by pathways such as base excision repair (BER), mismatch repair (MMR), homologous recombination, Fanconi anaemia and translesion DNA synthesis (TLS).
3. Diverse cellular pathways collectively modulate alkylation sensitivity, and imbalances within or between these pathways can have deleterious consequences at the cellular and whole-animal levels.
4. Developing agents to modulate DNA repair pathways is a promising strategy to increase the effectiveness of current chemotherapeutic alkylating agents.
5. Investigation of DNA repair capacity in cancer patients may provide crucial information about which chemotherapeutic therapies to use, because differences can result in drastic variation in alkylation sensitivity.

要点翻译：

1. 化疗烷化剂会在DNA上诱导产生一系列细胞毒性和致突变性加合物。
2. 烷化剂引起的DNA损伤可通过不同细胞机制进行感知和修复，包括通过AlkB同源物（ALKBH）家族和O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）蛋白的直接修复，或通过碱基切除修复（BER）、错配修复（MMR）、同源重组、范可尼贫血和跨损伤DNA合成（TLS）等途径。
3. 多种细胞通路共同调控烷化损伤敏感性，这些通路内部或通路之间的失衡可能在细胞和整体动物水平产生有害后果。
4. 开发调控DNA修复通路的制剂是提高现有化疗烷化剂疗效的有效策略。
5. 对癌症患者DNA修复能力的检测可为化疗方案选择提供关键信息，因为修复能力的差异可能导致烷化损伤敏感性的显著变化。

英文摘要：

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

摘要翻译： 

烷化剂是一类主要的化疗药物，其通过造成细胞毒性DNA损伤作为主要作用模式，同时伴随致突变性损伤。多种细胞通路，包括直接DNA损伤逆转、碱基切除修复（BER）和错配修复（MMR），会对烷化损伤作出反应，以防御烷化剂诱导的细胞死亡或突变。然而，维持这些通路内部及相互之间活性的适当平衡，对于机体对烷化剂产生良好反应至关重要。此外，个体对烷化剂的反应在不同组织间以及不同个体间可能存在显著差异，这提示存在调控烷化剂毒性的遗传和表观遗传机制。

原文链接：

Balancing repair and tolerance of DNA damage caused by alkylating agents