Evaluation of a 7-day continuous intravenous infusion of decitabine: Inhibition of promoter-specific and global genomic DNA methylation
Evaluation of a 7-day continuous intravenous infusion of decitabine: Inhibition of promoter-specific and global genomic DNA methylation
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DOI：
10.1200/jco.2005.06.118
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发表时间：
2005-06-10
影响因子：
45.3
通讯作者：
Karpf, AR
中科院分区：
文献类型：
--
作者：
Samlowski, WE;Leachman, SA;Karpf, AR
目的核苷类似物5-氮杂-2 '-脱氧胞苷（5-aza-CdR，decitabine）是一种有效的DNA甲基化抑制剂。用该试剂进行细胞处理诱导甲基化沉默基因的重新表达。目前还不清楚这种化合物在体内抑制DNA甲基化的程度。为探讨地西他滨持续静脉滴注1周对实体瘤患者的分子生物学效应和毒性作用，对10例难治性实体瘤患者进行了临床研究。地西他滨以2 mg/kg/d连续输注给药168小时。定量聚合酶链反应和高效液相色谱法被用来测量启动子特异性和全球的DNA甲基化在外周血细胞治疗before and after treatment.Results短暂的III/IV级中性粒细胞减少症（2例）和II级血小板减少症（1例），观察到在最低计划剂量步骤（2/d，7天）。未观察到非血液学毒性。定量聚合酶链反应显示，在所有13个治疗周期中，治疗开始后14天，法师-1启动子显著低甲基化。在分析的13个治疗周期中的11个中，到第14天也观察到显著的基因组DNA低甲基化。基因组DNA甲基化恢复到基线水平的28至35天后，开始治疗，表明DNA甲基化的抑制地西他滨是transient.Conclusion 168小时连续输注地西他滨是耐受性良好，并导致在体内抑制启动子特异性和基因组DNA甲基化。该治疗方案适用于评价地西他滨与其活性可通过逆转DNA甲基化介导的基因沉默而增强的药物的组合。
Purpose The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients.Methods Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/kg/d via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment.Results Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2/d for 7 days). Nonhematologic toxcithes were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient.Conclusion A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation-mediated gene silencing.