CLINICAL HISTONE DEACETYLASE INHIBITION AND RETINOIDS

组蛋白乙酰化的动态变化显著调节 各种基因的转录。组蛋白的脱乙酰化 组蛋白脱乙酰酶(HDAC)的募集似乎起着重要的作用 机制在血液系统恶性肿瘤中的作用。药理上的抑制作用 HDAC可能有助于逆转恶性表型。假定的区分 苯丁酸钠(PB)诱导组蛋白乙酰化 在体内保持的浓度。在体外系统中，HDAC的抑制剂 在维甲酸反应系统中与维甲酸协同作用。维甲酸是 在髓系分化中至关重要。铅和全反式维甲酸 (ATRA)在ML-1髓系白血病细胞系中显示出显著的协同作用，该细胞株具有 为髓系恶性肿瘤的PB的临床前发展奠定了基础。 这项申请中提出的研究开始了对 PB联合全反式维甲酸治疗骨髓增生异常增殖症(MDS)和高危急性加重期 相关公司支持的一项1期研究的髓系白血病(AML) 生物学研究。联合用药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 将对毒品进行调查。生物终点将被指示以确定 PB加ATRA给药是否会导致预期的药效学 效果。这些包括在外周血中诱导组蛋白乙酰化和 骨髓单个核细胞，诱导p21WAF1/CIP1表达，以及 骨髓增殖分化的下游变化。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的面积 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髓系中的第二阶段试验 目前几乎没有有效治疗方法的恶性肿瘤。

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.