PURPOSE:In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects. METHODS:In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs. RESULTS:Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary. CONCLUSION:HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far.

译文

目的:在染色质结构和组蛋白功能的调节中,组蛋白脱乙酰基酶(HDACs)是关键酶,因此是表观遗传调节和基因表达的调节剂。 HDAC抑制剂伏立诺他进入细胞内区室对于发挥表观遗传学作用至关重要。
方法:使用经验证的LC / MS / MS测定法对接受口服Zolinza(400 mg qd)血浆和外周血单核细胞(PBMC)浓度的伏立诺司他浓度的10例肉瘤患者进行定量,以确定细胞内和细胞外药代动力学数据。使用荧光测定法评估细胞的HDAC活性。 PBMC中细胞内和细胞外伏立诺他浓度与HDAC抑制之间建立了浓度-反应关系。
结果:伏立诺他及其两种主要的非活性代谢产物在8小时内在血浆和PBMC中的药代动力学被确定。稳态AUC(±SD)和T1 / 2(±SD)计算为4.61±0.87 h M和1.73±0.69 h(血浆)和15.2±9.03 h µM和5.30±4.27 h(PBMC)。确定了伏立诺他在PBMC中的细胞内蓄积以及伏立诺他的长期消除。细胞HDAC抑制与血浆和PBMC中的伏立诺他浓度平行增加。为了有效抑制细胞HDAC(IC50),需要使用伏立诺司他在血浆中的浓度为0.05 µM,在PBMC中的浓度为0.17 µM。
结论:HDAC的抑制作用与细胞内伏立诺他浓度密切相关且持续时间短,这可能是迄今为止迄今为止在实体瘤中伏立诺他所见疗效有限的原因。

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