Lin Jianqing, Gilbert Jill, Rudek Michelle A, Zwiebel James A, Gore Steve, Jiemjit Anchalee, Zhao Ming, Baker Sharyn D, Ambinder Richard F, Herman James G, Donehower Ross C, Carducci Michael A
Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Clin Cancer Res. 2009 Oct 1;15(19):6241-9. doi: 10.1158/1078-0432.CCR-09-0567. Epub 2009 Sep 29.
This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.
Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC.
The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies.
The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.
这是一项I期试验，旨在确定5-氮杂胞苷（5-AC）与苯丁酸钠联合用于难治性实体瘤患者的最小有效剂量和最佳给药方案。同时还研究了其药代动力学、药效学和抗肿瘤作用。
对27例晚期实体瘤患者研究了三种给药方案，并记录毒性反应。评估了联合用药的药代动力学。对重复的肿瘤活检组织和外周血单个核细胞（PBMC）进行分析，以评估治疗反应中的表观遗传学变化。评估EBV滴度作为PBMC中表观遗传调控基因重新表达的替代指标。
5-AC和苯丁酸钠的三种剂量方案总体耐受性良好且安全。共对27例患者进行了48个周期的给药。最常见的毒性反应是与骨髓抑制相关的中性粒细胞减少和贫血，程度较轻。联合用药的临床缓解率令人失望。1例患者疾病稳定5个月，而26例患者疾病进展为最佳肿瘤反应。苯丁酸钠和5-AC的给药似乎未改变任何一种药物的药代动力学。尽管在配对活检或PBMC中有个别靶向DNA甲基转移酶活性和组蛋白H3/4乙酰化变化的病例，但基于这些有限的相关性研究无法得出确凿结论。
5-AC和苯丁酸钠在三种给药方案下联合应用总体耐受性良好且安全，但缺乏临床获益的实际证据。
