Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo
Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo
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DOI：
10.1158/1078-0432.ccr-05-1225
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Houghton, PJ
中科院分区：
文献类型：
--
作者：
Graham, C;Tucker, C;Houghton, PJ
目的：组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）控制组蛋白和其他调节转录和蛋白质功能的蛋白质的乙酰化状态。已经开发了几种结构不同的HDAC抑制剂作为癌症治疗剂，并且在体外已经显示出引起分化、细胞周期停滞或凋亡。在这里，我们评估了缩肽（一种天然四肽HDAC抑制剂）对一组儿科实体瘤模型的体内作用，并评估了药代动力学和药效学变量与肿瘤敏感性。以最大耐受剂量给予缩酚肽（4.4 mg/kg，每7天给药一次，每21天重复3次静脉注射，共2个周期（9例脑肿瘤，11例肾癌，9例横纹肌肉瘤，3例神经母细胞瘤和7例骨肉瘤）。药代动力学变量进行了测定，如组蛋白和p53乙酰化，诱导p53和p53基因型，和Akt磷酸化的改变的变化。结果：39个肿瘤评估，三个显示客观肿瘤消退[两个脑肿瘤（原始神经外胚层肿瘤和非典型畸胎样恶性横纹肌样肿瘤）和一个肾母细胞瘤]。缩肽抑制许多肿瘤系的生长，但仅在两种肿瘤模型（间变性星形细胞瘤、两种横纹肌肉瘤和一种Wilms肿瘤）中实现稳定的疾病（在治疗周期1期间体积增加<25%）。药代动力学分析显示，人群估计AUC（0 - 24）为1，123 ng h/mL，与正在进行的I期试验中13 mg/m2的暴露量相似。组蛋白乙酰化（H2A、1 - 1213、H3和H4）在三种缩肽敏感性和三种固有耐药肿瘤中的药效学变化遵循相似的模式;组蛋白乙酰化的最大增加发生在8小时，并升高长达96小时。在两个敏感的肿瘤细胞系中，IRS56和BT27（均为野生型p53）p53在治疗的肿瘤中增加，在8小时时达到最大值，并与p21（cip1）的诱导相关，而p53在突变型p53的肿瘤中稳定。对缩肽的敏感性与p53基因型、p53乙酰化、裂解的聚（ADP-核糖）聚合酶或Akt磷酸化（Ser（473））无关。结论：我们的研究结果表明缩肽在体内抑制其靶点，导致组蛋白乙酰化增加;然而，这与药物敏感性无关。在临床相关药物暴露的剂量水平下给药的客观缓解率相对较低[39个肿瘤细胞系中有3个（8%）显示大于或等于部分缓解，4个（10%）疾病稳定]表明，作为单药，缩肽在一线环境中对儿科实体瘤的临床效用可能有限。
Purpose: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating transcription and protein function. Several structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity.Experimental Design: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days x 3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors, 11 kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction of p53 and p53 genotype, and alterations in Akt phosphorylation.Results: Of 39 tumors evaluated, three showed objective tumor regressions [two brain tumors (primitive neuroectodermal tumor and atypical teratoid malignant rhabdoid tumor) and one Wilms' tumor]. Depsipeptide inhibited growth of many tumor lines but achieved stable disease (< 25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas, and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC(0-24) was 1,123 ng h/mL, similar to the exposure following 13 mg/m(2) in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, 1-1213, H3, and H4) in three depsipeptide-sensitive and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at 8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased in treated tumors being maximal at 8 hours and associated with induction of p21(cip1), whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation, cleaved poly (ADP-ribose) polymerase, or phosphorylation of Akt (Ser(473)).Conclusions: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity. The relatively low objective response rate [3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease] administered at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited clinical utility against pediatric solid tumors in a first-line setting.