A phase I trial of depsipeptide (FR901228) in patients with advanced cancer.
A phase I trial of depsipeptide (FR901228) in patients with advanced cancer.
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DOI：
10.1046/j.1359-4117.2002.01039.x
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发表时间：
2002-11-01
影响因子：
--
通讯作者：
Hawkins, Michael J
中科院分区：
文献类型：
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作者：
Marshall, John L;Rizvi, Naiyer;Hawkins, Michael J
Depsipeptide (FR901228) 是一种从紫色色杆菌中分离出来的双环肽，已证明对人肿瘤细胞系具有有效的体外细胞毒活性，并且对人肿瘤异种移植物具有体内功效。主要作用机制是通过抑制组蛋白脱乙酰酶。由于严重的心脏毒性，最初的开发被停止。美国国家癌症研究所进行的后续研究表明，通过改变给药方案，可以实现无心脏毒性的给药。 I 期试验旨在确定每周 3 次 4 小时输注并休息一周时的最大耐受剂量和毒性特征。 33 名患有晚期、无法治愈的癌症的患者被纳入该试验，并接受剂量范围为 1 mg/m2 至 17.7 mg/m2 的 Depsipeptide 治疗。当剂量高于 5 mg/m2 时，我们观察到恶心、呕吐、疲劳和厌食等常见症状。几名患者的心电图发生了微妙的变化。然而，没有观察到心肌酶异常或射血分数降低。 MTD 定义为 13.3 mg/m2，剂量限制性毒性为 3 级血小板减少症和疲劳。当以 4 小时输注形式给药时，缩酚肽可以安全地给药，并且需要进一步的临床试验。
Depsipeptide (FR901228) is a bicyclic peptide isolated from Chromobacterium violaceum that has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. The primary mechanism of action is through inhibition of histone deacetylase. Initial development was halted due to significant cardiac toxicity. Subsequent studies performed at the National Cancer Institute demonstrated administration without cardiotoxicity was possible by varying the schedule of administration. A phase I trial was designed to determine the maximum tolerated dose and toxicity profile when administered as a 4-hour infusion weekly x 3 with one week rest. 33 Patients with advanced, incurable cancers were enrolled into this trial and treated with doses of Depsipeptide ranging from 1 mg/m2 to 17.7 mg/m2. At doses above 5 mg/m2, we observed common symptoms of nausea, vomiting, fatigue, and anorexia. Subtle changes in ECGs were seen in several patients. However, no cardiac enzyme abnormalities or reduction in ejection fraction were observed. The MTD was defined as 13.3 mg/m2 with dose limiting toxicities being grade 3 thrombocytopenia and fatigue. Depsipeptide can be safely administered when given as a 4-hour infusion and further clinical trials are warranted.