CLINICAL HISTONE DEACETYLASE INHIBITION AND RETINOIDS

组蛋白乙酰化的动态变化显著调节 多种基因的转录。组蛋白的脱乙酰化 组蛋白去乙酰化酶（HDAC）的募集似乎在 在造血系统恶性肿瘤中的机制作用。的药理学抑制 HDAC可能有助于逆转恶性表型。假定的差异 苯丁酸钠（PB）诱导骨髓细胞中组蛋白乙酰化 在体内维持浓度。在体外系统中，HDAC的抑制剂 在类维生素A反应系统中与类维生素A协同作用。类维生素a 在骨髓分化中至关重要。PB和全反式维甲酸 （ATRA）在ML-1髓性白血病细胞系中显示出显著的协同作用， 为PB在骨髓恶性肿瘤中的临床前开发奠定了基础。 本申请中提出的研究开始了 PB联合ATRA治疗骨髓增生异常综合征（MDS）和高危急性骨髓增生异常综合征 骨髓性白血病（AML）通过相关支持的1期研究 生物学研究。该组合的临床可行性和毒性 将进行研究，并研究两者之间的潜在药代动力学相互作用 毒品将被调查。将指导生物学终点以确定 PB + ATRA给药是否导致预测的药效学 方面的影响.这些包括外周血中组蛋白乙酰化的诱导， 骨髓单个核细胞，诱导p21 WAF 1/CIP 1表达，和 骨髓增殖和分化的下游变化。变化 生物学和临床参数将与药代动力学相关 测量包括稳态浓度和等离子体下面积 浓度-时间曲线成功建立PB/ATRA组合 方案将导致这种组合在耐药骨髓细胞中的II期试验 目前几乎没有有效治疗的恶性肿瘤。

Dynamic changes in histone acetylation significantly regulate transcription of a variety of genes. Deacetylation of histones through recruitment of histone deacetylase enzymes (HDAC) appears to play an important mechanistic role in hematopoietic malignancies. Pharmacologic inhibition of HDAC may help reverse the malignant phenotype. The putative differentiating agent sodium phenylbutyrate (PB) induces histone acetylation in myeloid cells at concentrations maintained in vivo. In in vitro systems, inhibitors of HDAC synergize with retinoids in retinoid-responsive systems. Retinoids are critically important in myeloid differentiation. PB and all trans-retinoic acid (ATRA) show marked synergy in the ML-1 myeloid leukemia cell line, which has formed a foundation for pre-clinical development of PB in myeloid malignancies. The research proposed in this application begins the clinical development of the combination of PB plus ATRA in myelodysplasia (MDS) and high-risk acute myeloid leukemia (AML) through a Phase 1 study supported by correlative biological studies. The clinical feasibility and toxicity of this combination will be studied, and potential pharmacokinetic interactions between the two drugs will be investigated. Biological endpoints will be directed to determine whether administration of PB plus ATRA leads to predicted pharmacodynamic effects. These include induction of histone acetylation in peripheral blood and bone marrow mononuclear cells, induction of expression of p21WAF1/CIP1, and down-stream changes in bone marrow proliferation and differentiation. Changes in biological and clinical parameters will be correlated with pharmacokinetic measurements including steady state concentrations and area under the plasma concentration-time curve. Successful establishment of a PB/ATRA combination regimen will lead to Phase II trials of this combination in resistant myeloid malignancies for which few effective treatments are currently available.