Demethylating agents in myeloid malignancies.
Demethylating agents in myeloid malignancies.
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髓样恶性肿瘤中的脱甲基剂。
DOI：
10.1097/cco.0b013e328313699c
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发表时间：
2008-11
影响因子：
3.4
通讯作者：
Garcia-Manero G
中科院分区：
文献类型：
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作者：
Garcia-Manero G
两种去甲基化药物被批准用于治疗骨髓增生异常综合征 (MDS)：5-阿扎胞苷和 5-氮杂-2'-脱氧胞苷（地西他滨）。这些药物在结构上相关并诱导 DNA 低甲基化。异常的 DNA 甲基化与基因沉默有关。有人提出，低甲基化剂通过诱导表观遗传沉默基因的重新表达来发挥作用。在这里，我们提供这些药物的临床经验的最新总结。 5-阿扎胞苷和地西他滨根据临床反应在美国获得批准，但没有记录到对生存的影响。一项 III 期研究的最新结果表明，用 5-阿扎胞苷治疗高危 MDS 患者可显着改善总体生存率。地西他滨随机生存研究的结果将于 2007 年公布。表观遗传联合疗法（一种低甲基化药物与组蛋白脱乙酰酶抑制剂）的报告表明，这些疗法对 MDS/AML 患者具有显着的活性。随机研究正在测试联合用药优于单药治疗的概念。去甲基化药物是高危 MDS 患者的标准治疗方法，也是已知唯一能改善 MDS 自然史的药物。新联合疗法的进一步研究可能会导致MDS患者的治疗取得进一步进展。
Two demethylating agents are approved in myelodysplastic syndromes (MDS): 5-azacitidine and 5-aza-2′-deoxycitidine (decitabine). These drugs are structurally related and induce DNA hypomethylation. Aberrant DNA methylation is associated with gene silencing. It is proposed that hypomethylating agents work by inducing re-expression of epigenetically silenced genes. Here, we provide an up-to-date summary of the clinical experience with these drugs. 5-azacitidine and decitabine were approved in the US based on clinical responses but no effect on survival was documented. Recent results from a phase III study have indicated that treatment of patients with higher-risk MDS with 5-azacitidine results in significant improvement in overall survival. Results of a randomized survival study of decitabine should be available in 2007. Reports of combination epigenetic therapies (a hypomethylating agent with a histone deacetylase inhibitor) indicate that these have significant activity in patients with MDS/AML. Randomized studies are testing the concept that the combinations are superior to single agent therapy. Demethylating agents are the standard of care for patients with higher-risk MDS and the only agents known to improve the natural history of MDS. Further work in new combination therapies may result in further advances in the care of patients with MDS.