Felix C A
Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Med Pediatr Oncol. 2001 May;36(5):525-35. doi: 10.1002/mpo.1125.
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-re-ligation 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 II-mediated chromosomal breakage may be relevant to translocations in addition to this anti-neoplastic, 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.
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，包括蒽环类药物和放线菌素，都是高效的抗癌药物。所有这些药物都与一种独特形式的白血病相关，其特征是染色体易位作为一种治疗并发症。大多数易位会破坏位于11q23染色体带的MLL基因的一个断裂点簇区域（bcr）。其他特征性易位也可能发生。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。这些复合物降低了重新连接速率，破坏了切割 - 重新连接平衡，并具有增加切割的净效应。增加的切割会损害DNA并导致染色体断裂。具有无法修复的DNA损伤的细胞通过凋亡死亡。DNA拓扑异构酶II抑制剂与白血病的关联表明，除了这种抗肿瘤细胞毒性作用外，药物诱导的、DNA拓扑异构酶II介导的染色体断裂可能与易位有关。流行病学研究、基因组易位断点克隆和体外DNA拓扑异构酶II切割试验共同得出了一个与治疗相关的白血病模型，其中DNA拓扑异构酶II导致染色体断裂，当断裂被修复时易位形成。
