文章：

靶向DNA拓扑异构酶II在癌症化疗中的应用

Targeting DNA topoisomerase II in cancer chemotherapy

原文发布日期：2009-04-20

DOI: 10.1038/nrc2607

类型: Review Article

开放获取: 否

要点：

1. Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the epipodophyllotoxin etoposide and the anthracycline doxorubicin.
2. Most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex. Therefore, the principal action of the TOP2-targeting drugs that are currently used is to generate enzyme-mediated DNA damage.
3. A recent structure of the breakage reunion domain of TOP2 bound to DNA has been determined. This structure is likely to be useful for understanding the protein determinants of the action of drugs targeting TOP2. A drug–protein–DNA ternary complex would be valuable but has not yet been determined.
4. TOP2-mediated DNA damage is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein–DNA adducts.
5. Sensitivity to TOP2-targeting drugs depends in part on the levels of TOP2. Cells overexpressing TOP2 are hypersensitive to TOP2 poisons and cells expressing low levels of TOP2 are drug resistant. TOP2A is frequently co-amplified with ERBB2, which can lead to the development of tumours with increased levels of TOP2α.
6. An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations. TOP2β might be the TOP2 isoform that is most responsible for the secondary malignancies caused by TOP2-targeting drugs.
7. Anthracycline use is limited by cardiotoxicity. Although the mechanism of the cardiotoxicity is poorly understood, recent results suggest that anthracyclines that target TOP2β might contribute to cardiotoxicity. There might be considerable benefit to developing TOP2-targeting drugs that are specific for the TOP2α isoform.
8. Catalytic inhibition of TOP2 could also be a useful anticancer strategy. New compounds are being developed to test this possibility.

要点翻译：

1. 拓扑异构酶II（TOP2）是几类重要抗癌药物的作用靶点，包括表鬼臼毒素衍生物依托泊苷和蒽环类多柔比星。
2. 大多数靶向TOP2的临床有效药物通过捕获称为“共价复合物”的酶中间体来杀伤细胞。因此，目前使用的TOP2靶向药物的主要作用是产生酶介导的DNA损伤。
3. 最近解析了TOP2断裂再连接域与DNA结合的结构。该结构可能有助于理解TOP2靶向药物作用的蛋白质决定因素。虽然药物-蛋白质-DNA三元复合物具有重要价值，但尚未成功解析。
4. TOP2介导的DNA损伤通过多种修复通路进行修复。这类DNA损伤包括DNA链断裂和与DNA共价结合的蛋白质。修复TOP2介导的损伤需要双链断裂修复通路及专门去除蛋白质-DNA加合物的其他通路。
5. 对TOP2靶向药物的敏感性部分取决于TOP2的表达水平。过表达TOP2的细胞对TOP2毒剂高度敏感，而低表达TOP2的细胞则具有耐药性。TOP2A常与ERBB2共同扩增，这可能促进TOP2α水平升高的肿瘤发生。
6. 使用TOP2毒剂靶向TOP2的重要副作用是可能诱发继发性恶性肿瘤，这些肿瘤源于药物诱导的染色体易位。TOP2β可能是导致TOP2靶向药物引发继发性恶性肿瘤的主要亚型。
7. 蒽环类药物的临床应用受心脏毒性限制。虽然心脏毒性机制尚未明确，但最新研究表明靶向TOP2β的蒽环类药物可能参与心脏毒性发生。开发特异性靶向TOP2α亚型的药物可能带来显著获益。
8. TOP2的催化抑制也可能成为有效的抗癌策略。目前正在开发新型化合物以验证这一可能性。

英文摘要：

Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

摘要翻译： 

最近的分子研究扩展了拓扑异构酶II（TOP2）在生物学背景下的关键功能，包括DNA复制、转录和染色体分离。尽管TOP2的生物学功能对确保基因组完整性至关重要，但干扰TOP2并产生酶介导的DNA损伤的能力是癌症化疗的有效策略。使理解TOP2生物学功能的分子工具也正被用于理解药物作用的细节。这些研究有望实现对TOP2的精准靶向，作为一种有效的抗癌策略。

原文链接：

Targeting DNA topoisomerase II in cancer chemotherapy