Kelly Wm Kevin, Richon Victoria M, O'Connor Owen, Curley Tracy, MacGregor-Curtelli Barbara, Tong William, Klang Mark, Schwartz Lawrence, Richardson Stacie, Rosa Eddie, Drobnjak Marija, Cordon-Cordo Carlos, Chiao Judy H, Rifkind Richard, Marks Paul A, Scher Howard
Genitourinary Oncology Service, Departments of Medicine, Memorial Sloan-Kettering Cancer Center and Joan and Sanford Weill Medical College of Cornell University, New York, New York 10021, USA.
Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3578-88.
To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer.
SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues.
No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms.
Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
评估晚期癌症患者经2小时静脉输注给予辛二酰苯胺异羟肟酸（SAHA）的安全性、药代动力学和生物学活性。
A部分中，SAHA每21天给药3天；B部分中，给药5天，持续1至3周。实体瘤和血液系统恶性肿瘤患者（仅B部分）的剂量递增独立进行。进行药代动力学研究，并评估外周血单核细胞和肿瘤组织中乙酰化组蛋白的情况。
A部分入组的8例患者（75、150、300、600和900mg/m²/天）未观察到剂量限制性毒性。B部分入组的12例血液系统和17例实体瘤患者（300、600和900mg/m²/天）中，600mg/m²/天×5天×3周治疗方案下，5例血液系统患者中有2例因3/4级白细胞减少和/或血小板减少，治疗延迟≥1周。血液系统患者的最大耐受剂量为300mg/m²/天×5天×3周。1例实体瘤患者接受了900mg/m²/天×5天×3周的治疗方案，出现急性呼吸窘迫和3级低血压。该队列扩大至6例患者，未观察到其他剂量限制性毒性。平均终末半衰期为21至58分钟，曲线下面积呈剂量比例增加。在较高剂量水平下，观察到输注后4小时内外周血单核细胞中乙酰化组蛋白的蓄积。治疗后肿瘤活检通过免疫组化显示乙酰化组蛋白的蓄积。4例患者（2例淋巴瘤和2例膀胱癌）出现客观肿瘤退缩，肿瘤相关症状有临床改善。
每日静脉输注SAHA耐受性良好，可在体内抑制生物学靶点，对实体瘤和血液系统肿瘤具有抗肿瘤活性。
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