Leukemias related to treatment with DNA topoisomerase II inhibitors
Leukemias related to treatment with DNA topoisomerase II inhibitors
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DOI：
10.1002/mpo.1125
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发表时间：
2001-05-01
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影响因子：
--
通讯作者：
Felix, CA
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作者：
Felix, CA
表鬼臼毒素依托泊苷和替尼泊苷以及其他DNA拓扑异构酶II抑制剂，包括蒽环类和更生霉素是高效的抗癌药物。所有这些都与一种独特的白血病有关，其特征是作为治疗并发症的染色体易位。大多数易位破坏染色体带11 q23处MLL基因的断点簇区域（bcr）。也可能发生其他特征性易位。核酶DNA拓扑异构酶II的正常功能是通过瞬时切割和重新连接双螺旋的两条链来催化DNA拓扑结构在松弛状态和超螺旋状态之间的变化。作为DNA拓扑异构酶II抑制剂的抗癌药物具有细胞毒性，因为它们与DNA和DNA拓扑异构酶II形成复合物。复合物降低再连接速率，破坏裂解-再连接平衡，并具有增加裂解的净效应。增加的切割损伤DNA并导致染色体断裂。具有不可修复的DNA损伤的细胞通过凋亡而死亡。DNA拓扑异构酶II抑制剂与白血病的关联表明，药物诱导的DNA拓扑异构酶It介导的染色体断裂可能与易位有关，除了这种抑制性细胞毒性作用。流行病学研究、基因组易位断裂点克隆和体外DNA拓扑异构酶II切割测定一起导致治疗相关白血病的模型，其中DNA拓扑异构酶II引起染色体断裂，并且当断裂被修复时形成易位。儿科医学Oncol. 36：525-535，2001. (C)2001 Wiley-Liss，Inc.
The epipodophyllotoxins etoposide and teniposide and other DNA topoisomerase II inhibitors including anthracyclines and dactinomycin are highly efficacious anticancer drugs. All are associated with a distinct form of leukemia characterized by chromosomal translocations as a treatment complication. Most of the translocations disrupt a breakpoint cluster region (bcr) of the MLL gene at chromosome band 11q23. Other characteristic translocations also may occur. The normal function of the nuclear enzyme DNA topoisomerase II is to catalyze changes in DNA topology between relaxed and supercoiled states by transiently cleaving and re-ligating both strands of the double helix. Anticancer drugs that are DNA topoisomerase II inhibitors are cytotoxic because they form complexes with DNA and DNA topoisomerase II. The complexes decrease the re-ligation rate, disrupt the cleavage-religation equilibrium, and have a net effect of increasing cleavage. The increased cleavage damages the DNA and leads to chromosomal breakage. Cells with irreparable DNA damage die by apoptosis. The association of DNA topoisomerase II inhibitors with leukemia suggests that the drug-induced, DNA topoisomerase It-mediated chromosomal breakage may be relevant to translocations in addition to this antineoplastic, cytotoxic action. Epidemiological studies, genomic translocation breakpoint cloning and in vitro DNA topoisomerase II cleavage assays together lead to a model for treatment-related leukemia in which DNA topoisomerase II causes chromosomal breakage and translocations form when the breakage is repaired. Med. Pediatr. Oncol. 36:525-535, 2001. (C) 2001 Wiley-Liss, Inc.