Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome
Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome
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DOI：
10.1038/sj.leu.2404050
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发表时间：
2006-02-01
期刊：
影响因子：
11.4
通讯作者：
Nimer, S
中科院分区：
文献类型：
--
作者：
Maslak, P;Chanel, S;Nimer, S
肿瘤发生的表观遗传学机制最近作为人类癌症的潜在治疗靶点受到了极大的关注。我们设计了一项先导性研究，通过在急性髓系白血病(AML)或骨髓增生异常综合征(MDS)患者中顺序给予5-氮胞苷和苯丁酸钠(PB)来靶向DNA甲基化和组蛋白去乙酰化。10例可评价的患者(8例AML，2例MDS)连续7天皮下注射5-氮胞苷75 mg/m2，然后静脉注射PB钠5天，剂量为200 mg/kg。5名患者(50%)能够实现有益的临床反应(部分缓解或病情稳定)。一名MDS患者进行了异基因干细胞移植，39个月后存活下来，没有疾病的证据。联合方案耐受性良好，常见的不良反应有注射部位皮肤反应(90%的患者)和PB钠输注引起的嗜睡/疲劳(80%的患者)。相关的实验室研究证实了组蛋白H4的持续重乙酰化，尽管不能证明与临床反应有关。这项初步研究的结果表明，针对不同转录调控机制的联合方法在临床上是可行的，具有可接受的毒性和可测量的生物和临床结果。
Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients ( eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response ( partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.