Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia.
Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia.
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DOI：
10.1158/1078-0432.ccr-08-1007
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Stock W
中科院分区：
文献类型：
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作者：
Odenike OM;Alkan S;Sher D;Godwin JE;Huo D;Brandt SJ;Green M;Xie J;Zhang Y;Vesole DH;Stiff P;Wright J;Larson RA;Stock W
组蛋白脱乙酰酶 (HDAC) 的募集是一种转录抑制机制，与急性髓系白血病 (AML) 的分化阻断有关。我们假设 HDAC 抑制剂罗米地辛可能导致转录去抑制、AML 中特定靶基因的上调以及白血病克隆的分化。该研究的主要目的是评估罗米地辛治疗晚期 AML 的安全性和有效性。根据已知是否存在招募 HDAC 的染色体异常（包括涉及核心结合因子 (CBF) 的染色体异常），将 20 名患者分为 A 组或 B 组。罗米地辛静脉注射。 28 天周期的第 1,8 和 15 天，剂量为 13 mg/m2/d。在连续时间点评估药效学终点。常见的不良反应为 1 至 2 级恶心、厌食和疲劳。在队列 A 中没有观察到抗白血病活性的客观证据。在队列 B 中，尽管按照标准标准没有出现临床反应，但在 7 名患者中有 5 名观察到了抗白血病活性。 2 名患者骨髓原始细胞清除，3 名患者骨髓原始细胞减少 > 50%。此外，在 B 组中，24 小时时，MDR1 (P = 0.005)、p15 (P = 0.01) 和 p14 (P < 0.0001) 表达显着增加。在队列 A 中，尽管 MDR1、p15 和 p14 表达有上调趋势，但这些变化并不具有统计学意义。罗米地辛在 CBF AML 中具有不同的抗白血病和分子活性。 CBF AML 药物的开发应侧重于针对基因沉默相关机制（例如 DNA 甲基化）的组合。
Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML. Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m2/d on days 1,8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points. Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a >50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P = 0.005), p15 (P = 0.01), and p14 (P < 0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant. Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.