Phase I trial of continuous infusion 5-aza-2′-deoxycytidine
Phase I trial of continuous infusion 5-aza-2′-deoxycytidine
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DOI：
10.1007/s00280-002-0563-y
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发表时间：
2003-03-01
影响因子：
3
通讯作者：
Weber, JS
中科院分区：
文献类型：
--
作者：
Aparicio, A;Eads, CA;Weber, JS
目的：确定一种副作用可接受的去甲基化药物5-aza-2′-脱氧胞苷（DAC）剂量，并采用实时荧光定量PCR技术研究其对肿瘤活检组织治疗前后相关基因甲基化模式的影响。方法：19例转移性实体瘤患者连续静脉输注DAC治疗72 h， 1-3天（28天周期）。在DAC开始前和开始后7天分别行肿瘤活检。结果：研究剂量水平分别为20、30、40 mg/m(2)。5名患者中有2名在40 mg/m(2)时发现4级中性粒细胞减少，6名患者中有1名在30 mg/m(2)时发现4级中性粒细胞减少。本研究未见客观反应。在30和40 mg/m(2)组中，达到了0.1至0.2 ma的稳态DAC水平。观察到甲基化的变化，但没有单一基因一致地显示出去甲基化的证据。结论：DAC在每天30mg /m(2)静脉输注72小时的剂量下是耐受的。观察基因甲基化的变化。
Purpose: To identify a dose of the demethylating agent 5-aza-2'-deoxycytidine (DAC) with acceptable side effects, and to study its effect on the, methylation patterns of relevant genes in tumor biopsies before and after treatment with a novel methylation assay using real-time PCR. Methods: A group of 19 patients with metastatic solid tumors were treated with DAC by continuous intravenous infusion over 72 h, days 1-3 of a 28-day cycle. Tumor biopsies were taken before and 7 days after starting DAC. Results: The dose levels studied were 20, 30 and 40 mg/m(2). Grade 4 neutropenia was found in two of five patients at 40 mg/m(2) and one of six patients at 30 mg/m(2). No objective responses were seen in this study. Steady-state DAC levels of 0.1 to 0.2 muM were achieved in the 30 and 40 mg/m(2) cohorts. Changes in methylation were observed, but no single gene consistently demonstrated evidence of demethylation. Conclusions: DAC was tolerated at a dose of 30 mg/m(2) per day for a 72-h intravenous infusion. Changes in gene methylation were observed.