治疗采用低甲基化药物和组蛋白去乙酰化酶抑制剂的体外基础：能否利用表观遗传学变化来监测治疗？
In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment?
机构信息
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD 21287, USA.
出版信息
Leuk Res. 2009 Dec;33 Suppl 2(Suppl 2):S2-6. doi: 10.1016/S0145-2126(09)70226-7.
Abstract
Hematopoietic disorders such as myelodysplastic syndromes (MDS) show a high frequency of methylation of tumor suppressor genes. DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine are used to target DNA methylation in MDS patients. Combining these drugs with histone deacetylase (HDAC) inhibitors in vitro resulted in synergistic tumor suppressor gene re-expression. Several phase I trials have examined methylation, gene expression and DNA damage as markers of clinical response to DNMT and HDAC inhibitors, with conflicting results. Trials are ongoing to investigate early methylation changes and DNA damage markers to understand the mechanisms of these drugs and as potential predictors of clinical response.
摘要
造血系统疾病如骨髓增生异常综合征（MDS）表现出肿瘤抑制基因高甲基化频率。DNA 甲基转移酶（DNMT）抑制剂，如阿扎胞苷和地西他滨，被用于靶向 MDS 患者的 DNA 甲基化。将这些药物与组蛋白去乙酰化酶（HDAC）抑制剂联合应用于体外可导致协同的肿瘤抑制基因再表达。几项 I 期临床试验已经研究了甲基化、基因表达和 DNA 损伤作为 DNMT 和 HDAC 抑制剂临床反应的标志物，结果存在矛盾。目前正在进行临床试验以研究早期甲基化变化和 DNA 损伤标志物，以了解这些药物的作用机制，并作为临床反应的潜在预测指标。
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