Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
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DOI：
10.1182/blood-2006-05-021873
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Karp, Judith E.
中科院分区：
文献类型：
--
作者：
Gojo, Ivana;Jiemjit, Anchalee;Karp, Judith E.
MS-275是一种苯甲酰胺衍生物，在临床前模型中具有有效的组蛋白脱乙酰酶（HDAC）抑制和抗肿瘤活性。我们在38例成人晚期急性白血病患者中进行了口服MS-275的I期试验。患者队列最初接受MS-275治疗，每周一次，每次2 mg/m2，每4周重复一次，剂量范围为4 - 8 mg/m2，13例患者接受治疗后，每周一次，每次4 mg/m2，每6周重复一次，剂量范围为8 - 10 mg/m2。最大耐受剂量为8 mg/m2，每周1次，共4周，每6周1次。剂量限制性毒性（DLT）包括感染和神经系统毒性，表现为步态不稳和嗜睡。其他常见的非DLT为疲乏、厌食、恶心、呕吐、低白蛋白血症和低钙血症。MS-275处理诱导骨髓单个核细胞中蛋白质和组蛋白H3/H4乙酰化、p21表达和caspase-3活化增加。未观察到经典标准的反应。我们的研究结果表明，MS-275有效地抑制HDAC在体内晚期髓性白血病患者，并应进一步测试，最好是在不太先进的疾病患者。
MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly x 2, repeated every 4 weeks from 4 to 8 mg/m(2), and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m(2). The maximum-tolerated dose was 8 mg/m(2) weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease.