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Topoisomerase Ⅱ and leukemia

机译:拓扑异构酶Ⅱ与白血病

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摘要

Type Ⅱ topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase Ⅱ poisons) in clinical use. Topoisomerase Ⅱ poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase Ⅱ-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type Ⅱ topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase Ⅱ poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
机译:Ⅱ型拓扑异构酶是必需的酶,可调节DNA的上,下缠绕,打结和缠结。这些酶除了具有至关重要的生理功能外,还成为一些临床上使用最广泛的抗癌药物(拓扑异构酶Ⅱ毒物)的靶标。拓扑异构酶Ⅱ通过增加作为正常反应中间体的共价酶裂解的DNA复合物的水平来杀死细胞。依托泊苷,阿霉素和米托蒽醌等药物是各种实体瘤和血液系统恶性肿瘤的一线治疗方法。不幸的是,它们的使用也与特定白血病的发生有关。包含依托泊苷或阿霉素的治疗方案与在染色体带11q23处发生重排的急性髓细胞性白血病的发生有关。在婴儿白血病中也有类似的重排现象,并且与自然存在的拓扑异构酶Ⅱ活性化合物含量高的妊娠期饮食有关。最后,包括米托蒽醌和表柔比星在内的治疗方案与特征为t(15; 17)重排的急性早幼粒细胞白血病相关。本文的第一部分将重点讨论Ⅱ型拓扑异构酶,并描述酶和药物作用的机理。第二部分将讨论拓扑异构酶Ⅱ毒物如何引发导致白血病的染色体断裂,以及将药物作用与其致白血病潜力分离的潜在方法。

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