A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer.
A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer.
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DOI：
10.1002/cncr.25204
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发表时间：
2010-09-01
期刊：
影响因子：
6.2
通讯作者：
Matei, Daniela E.
中科院分区：
文献类型：
--
作者：
Fang, Fang;Balch, Curt;Schilder, Jeanne;Breen, Timothy;Zhang, Shu;Shen, Changyu;Li, Lang;Kulesavage, Carol;Snyder, Anthony J.;Nephew, Kenneth P.;Matei, Daniela E.
异常DNA甲基化是癌症的一个标志，DNA甲基转移酶抑制剂在血液系统恶性肿瘤中已经证明了临床疗效。基于临床前研究表明，低甲基化药物可以逆转卵巢癌细胞的铂耐药，我们在复发的铂耐药卵巢癌患者中进行了一项低剂量地西他滨联合卡铂的I期试验。在28天周期的第8天卡铂（AUC 5）之前，每天静脉注射地西他滨，持续5天。使用标准的3+3剂量递增法，地西他滨在两个剂量水平下进行试验：10mg /m2（7例患者）或20mg /m2（3例患者）。在第1天（预处理）、第5天、第8天和第15天收集外周血单个核细胞（PBMCs）和血浆，用于评估全局（LINE-1重复元件）和基因特异性DNA甲基化。20 mg/m2剂量下的剂量限制性毒性（DLT）为4级中性粒细胞减少（2例），10 mg/m2剂量下未观察到DLT。最常见的毒性反应为恶心、过敏反应、中性粒细胞减少、疲劳、厌食、呕吐和腹痛，主要为1-2级。观察到1例完全缓解，另外3例患者病情稳定≥6个月。在第8天和第15天，在pbmc的DNA中检测到LINE-1低甲基化。在5个卵巢癌相关的甲基化基因中，HOXA11和BRCA1在第8天和第15天的血浆中去甲基化。重复低剂量地西他滨与卡铂联合用于卵巢癌患者是耐受的，并且显示出生物学活性（即dna低甲基化），证明进一步的临床疗效测试是合理的。
Aberrant DNA methylation is a hallmark of cancer and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. Based on preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, we conducted a phase I trial of low dose decitabine combined with carboplatin, in patients with recurrent, platinum-resistant ovarian cancer. Decitabine was administered i.v. daily for five days, prior to carboplatin (AUC 5) on day 8 of a 28-day cycle. Using a standard 3+3 dose escalation decitabine was tested at two dose levels: 10 mg/m2 (seven patients) or 20 mg/m2 (three patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on days 1 (pre-treatment), 5, 8, and 15, were utilized to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. Dose-limiting toxicity (DLT) at the 20 mg/m2 dose was grade 4 neutropenia (2 patients) and no DLTs were observed at 10 mg/m2. Most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and three additional patients had stable disease for ≥ six months. LINE-1 hypomethylation on days 8 and 15 was detected in DNA from PBMCs. Of five ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on days 8 and 15. Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (i.e., DNA-hypomethylating) activity justifying further testing for clinical efficacy.
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影响因子：
5.7
作者：
Balch, C;Yan, P;Nephew, KP
通讯作者：
Nephew, KP
DOI：
10.1111/j.1525-1438.2005.00130.x
发表时间：
2005-09-01
影响因子：
4.8
作者：
Duffy, MJ;Bonfrer, JM;Zwirner, M
通讯作者：
Zwirner, M
DOI：
10.1111/j.1525-1438.2007.01063.x
发表时间：
2008-07-01
影响因子：
4.8
作者：
Gadducci, A.;Tana, R.;Genazzani, A. R.
通讯作者：
Genazzani, A. R.
影响因子：
3.8
作者：
Helleman J;van Staveren IL;Dinjens WN;van Kuijk PF;Ritstier K;Ewing PC;van der Burg ME;Stoter G;Berns EM
通讯作者：
Berns EM
影响因子：
11.2
作者：
Hoque, MO;Begum, S;Sidransky, D
通讯作者：
Sidransky, D