Dassonneville L, Bailly C
Laboratoire de pharmacologie antitumorale, Centre Oscar-Lambret, Lille.
Bull Cancer. 1998 Mar;85(3):254-61.
The treatment of cancer with alkylating drugs or topoisomerase II inhibitors can be responsible for the development of myelodysplastic syndromes and acute myelogenous leukemia. Alkylating agents such as melphalan and cisplatinum mainly produce damages at chromosomes 5 and 7 whereas topoisomerase II inhibitors-induced lesions essentially affect chromosomes 11 and 21. Rearrangements of the MLL gene at band 11q23 are frequently observed in human de novo myeloid and lymphoid leukemia as well as in leukemia or myelodysplasia secondary to therapy with drugs targetting topoisomerase II such as the epipodophyllotoxins. A relationship between the treatment with etoposide on teniposide and the development of translocations of the MLL gene has been clearly evidenced. The potential molecular basis of the chromosomal rearrangements implicating topoisomerase II and its inhibitors are discussed. The chemical structure of the inhibitors, their mechanism of action and the genes targetted by these drugs are presented. DNA cleavages induced directly by topoisomerase II inhibitors or by the drug induced apoptotic cellular response are responsible for nonrandom chromosomal aberrations and contribute to leukemogenesis.
使用烷化剂或拓扑异构酶II抑制剂治疗癌症可能会导致骨髓增生异常综合征和急性髓性白血病的发生。诸如美法仑和顺铂等烷化剂主要在5号和7号染色体上产生损伤，而拓扑异构酶II抑制剂诱导的损伤主要影响11号和21号染色体。在人类原发性髓系和淋巴系白血病以及继发于使用靶向拓扑异构酶II的药物（如依托泊苷）治疗后的白血病或骨髓发育异常中，经常观察到11q23带处MLL基因的重排。已明确证实依托泊苷或替尼泊苷治疗与MLL基因易位的发生之间存在关联。文中讨论了涉及拓扑异构酶II及其抑制剂的染色体重排的潜在分子基础。介绍了抑制剂的化学结构、作用机制以及这些药物靶向的基因。拓扑异构酶II抑制剂直接诱导的DNA裂解或药物诱导的细胞凋亡反应导致了非随机染色体畸变，并促进了白血病的发生。
