Potential role of histone deacetylase inhibitors in mesothelioma: Clinical experience with suberoylanilide hydroxamic acid
Potential role of histone deacetylase inhibitors in mesothelioma: Clinical experience with suberoylanilide hydroxamic acid
复制标题
DOI：
10.3816/clc.2006.n.003
复制
发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Kelly, W. Kevin
中科院分区：
文献类型：
--
作者：
Krug, Lee M.;Curley, Tracy;Kelly, W. Kevin
背景：组蛋白脱乙酰酶抑制剂是一类新型治疗剂，可抑制组蛋白和其他参与基因表达和细胞周期进程调节的蛋白质的脱乙酰化。其中一种药物伏立诺他（辛二酰苯胺异羟肟酸[SAHA]）的静脉和口服制剂的 I 期试验表明，它是安全且可耐受的，它能抑制外周血单核细胞中的组蛋白脱乙酰化，并且具有广泛的抗肿瘤活性。患者和方法：13 名间皮瘤患者被纳入口服 SAHA 的 I 期试验。除一名外，其他人此前均接受过化疗。结果：4 名患者完成了≥6 个周期的治疗； 2 名患者表现出部分缓解。这组患者的毒性与整个 I 期试验中观察到的毒性相似：主要是疲劳、脱水、恶心和呕吐。结论：鉴于一线化疗后病情进展的晚期间皮瘤患者缺乏治疗选择，这些结果令人鼓舞。一项口服 SAHA 的安慰剂对照、随机 III 期研究现已针对培美曲塞治疗失败的间皮瘤患者开放。
BACKGROUND: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity. PATIENTS AND METHODS: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy. RESULTS: Four patients completed >= 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting. CONCLUSION: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.