Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Leukemia. 2011 Feb;25(2):226-35. doi: 10.1038/leu.2010.276. Epub 2010 Nov 30.
Epigenetic changes have been identified in recent years as important factors in the pathogenesis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Histone deacetylase inhibitors (HDACIs) regulate the acetylation of histones as well as other non-histone protein targets. Treatment with HDACIs results in chromatin remodeling that permits re-expression of silenced tumor suppressor genes in cancer cells, which, in turn, can potentially result in cellular differentiation, inhibition of proliferation and/or apoptosis. Several classes of HDACIs are currently under development for the treatment of patients with MDS and AML. Although modest clinical activity has been reported with the use of HDACIs as single-agent therapy, marked responses have been observed in selected subsets of patients. More importantly, HDACIs appear to be synergistic in vitro and improve response rates in vivo when combined with other agents, such as hypomethylating agents. Furthermore, HDACIs are also being investigated in combination with non-epigenetic therapies. This article synthesizes the most recent results reported with HDACIs in clinical trials conducted in patients with MDS and other myeloid malignancies.
近年来，表观遗传改变已被确定为骨髓增生异常综合征（MDS）和急性髓系白血病（AML）发病机制中的重要因素。组蛋白去乙酰化酶抑制剂（HDACIs）可调节组蛋白和其他非组蛋白蛋白靶标的乙酰化。HDACIs 的治疗可导致染色质重塑，从而使沉默的肿瘤抑制基因在癌细胞中重新表达，这反过来又可能导致细胞分化、抑制增殖和/或细胞凋亡。目前正在开发几类 HDACIs 用于治疗 MDS 和 AML 患者。尽管使用 HDACIs 作为单一药物治疗已报告了适度的临床活性，但在某些选定的患者亚组中观察到了明显的反应。更重要的是，HDACIs 似乎在体外具有协同作用，并与其他药物（如低甲基化剂）联合使用时可提高体内的反应率。此外，HDACIs 也正在与非表观遗传疗法联合进行研究。本文综合了在 MDS 和其他髓系恶性肿瘤患者的临床试验中报告的 HDACIs 的最新结果。
