Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay
Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay
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DOI：
10.1158/1078-0432.ccr-07-4427
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发表时间：
2008-06-01
影响因子：
11.5
通讯作者：
Li, Zuomei
中科院分区：
文献类型：
--
作者：
Bonfils, Claire;Kalita, Ann;Li, Zuomei
目的：通过新型全细胞 HDAC 酶测定，在临床前模型和患者中评估 MGCD0103（一种同型选择性组蛋白脱乙酰酶 (HDAC) 抑制剂）的药效学特性。实验设计：Boc-Lys(epsilon-Ac)-AMC，一种具有荧光读数的 HDAC 底物，被发现具有细胞渗透性，用于监测培养癌细胞中 MGCD0103 介导的 HDAC 抑制结果：MGCD0103 以剂量依赖性方式抑制体外多种人类癌细胞系和离体人外周 WBC 中的 HDAC 活性。与辛二酰苯胺异羟肟酸不同，MGCD0103 的 HDAC 抑制活性具有时间依赖性，并且在体外外周 WBC 中药物去除后可持续至少 24 小时。 MGCD0103 的抑制活性在小鼠体内持续至少 8 小时，在实体瘤患者体内持续 48 小时。 MGCD0103 在外周 WBC 中的 HDAC 抑制活性与小鼠血液和植入肿瘤中组蛋白乙酰化的诱导相关。在癌症患者中，MGCD0103 的持续药效作用只能通过外周 WBC 中剂量依赖性酶抑制来观察，而不能通过组蛋白乙酰化分析来观察。 结论：本研究表明 MGCD0103 具有持续的药效作用，可以通过基于细胞的 HDAC 酶测定在体外和体内进行监测。
Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay.Experimental Design: Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients.Results: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis.Conclusions: This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.