Inhibitors of DNA methylation: beyond myelodysplastic syndromes.
Inhibitors of DNA methylation: beyond myelodysplastic syndromes.
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DOI：
10.1038/ncponc0351
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发表时间：
2005-12-01
影响因子：
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通讯作者：
Fenaux, Pierre
中科院分区：
文献类型：
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作者：
Fenaux, Pierre
DNA甲基转移酶（DNMT）抑制剂阿扎胞苷（Vidaza，Pharmion，Boulder，CO，USA）和地西他滨（Dacogen; SuperGen Inc，都柏林，CA，USA和MGI Pharma Inc，布卢明顿，MN，USA）对骨髓增生异常综合征（MDS）的治疗模式具有显著影响，以前主要通过支持性护理和造血干细胞移植来管理。迄今为止在MDS中观察到的积极临床经验加上在治疗其他血液恶性肿瘤中面临的持续挑战，已经成为进一步探索DNMT抑制剂在MDS之外的治疗价值的动力。在这方面，这些药物的大部分数据都是在急性髓性白血病（AML）的背景下。在提交给FDA批准阿扎胞苷治疗MDS的临床试验中，也报告了这些药物治疗转化期原始细胞过多的难治性贫血患者（世界卫生组织重新分类为AML）的经验。在慢性髓细胞性白血病和急性淋巴细胞性白血病中也描述了一些用途。需要进一步的研究来阐明治疗白血病的适当剂量和周期数和持续时间，并确定理想的治疗候选者，探索DNMT抑制剂与其他药物，特别是组蛋白去乙酰化酶抑制剂联合使用的作用，描述市售药物之间的差异，并确定这些药物的长期安全性。为此，DNMT抑制剂在血液系统恶性肿瘤以外的MDS的经验进行审查，努力更好地了解这些药物的治疗潜力，并确定在这些设置未来的探索领域。
DNA methyltransferase (DNMT) inhibitors, azacitidine (Vidaza, Pharmion, Boulder, CO, USA) and decitabine (Dacogen; SuperGen Inc, Dublin, CA, USA, and MGI Pharma Inc, Bloomington, MN, USA), have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDSs), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation. The positive clinical experience seen in MDS to date coupled with the persistent challenges faced in the treatment of other hematologic malignancies has served as the impetus for further exploration of the therapeutic value of DNMT inhibitors beyond MDS. In that respect, the majority of data for these agents are in the setting of acute myelogenous leukemia (AML). Experience with these agents in patients with refractory anemia with excess blasts in transformation (reclassified by the World Health Organization as AML) was also reported in the clinical trials submitted to the FDA for approval of azacitidine for MDS. Some use has also been described in chronic myelogenous leukemia and acute lymphocytic leukemia. Further studies are needed to clarify the appropriate dose and the number and duration of cycles in the treatment of leukemias, and to identify ideal candidates for therapy, explore the role of DNMT inhibitors in combination with other agents, especially histone deacetylase inhibitors, delineate differences between the commercially available agents, and establish the long-term safety of these agents. To this end, experience with DNMT inhibitors in hematologic malignancies other than MDS is reviewed in an effort to better understand the therapeutic potential of these agents and to define areas of future exploration in these settings.