Gojo Ivana, Jiemjit Anchalee, Trepel Jane B, Sparreboom Alex, Figg William D, Rollins Sandra, Tidwell Michael L, Greer Jacqueline, Chung Eun Joo, Lee Min-Jung, Gore Steven D, Sausville Edward A, Zwiebel James, Karp Judith E
University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Blood. 2007 Apr 1;109(7):2781-90. doi: 10.1182/blood-2006-05-021873.
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/m2, and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 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.
MS-275是一种苯甲酰胺衍生物，在临床前模型中具有强大的组蛋白脱乙酰酶（HDAC）抑制和抗肿瘤活性。我们对38例晚期急性白血病成人患者进行了口服MS-275的1期试验。患者队列最初接受MS-275治疗，每周一次，共2次，每4周重复一次，剂量从4至8mg/m²；在13例患者接受治疗后，改为每周一次，共4次，每6周重复一次，剂量从8至10mg/m²。最大耐受剂量为每6周8mg/m²，每周一次，共4周。剂量限制性毒性（DLT）包括感染以及表现为步态不稳和嗜睡的神经毒性。其他常见的非DLT包括疲劳、厌食、恶心、呕吐、低白蛋白血症和低钙血症。MS-275治疗可诱导骨髓单个核细胞中蛋白质和组蛋白H3/H4乙酰化增加、p21表达增加以及半胱天冬酶-3激活。未观察到符合经典标准的反应。我们的结果表明，MS-275在晚期髓系白血病患者体内可有效抑制HDAC，应进一步进行试验，最好在病情较轻的患者中进行。
