Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors
Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors
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DOI：
10.1200/jco.2005.12.085
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发表时间：
2005-03-20
影响因子：
45.3
通讯作者：
Wilson, RH
中科院分区：
文献类型：
--
作者：
Grem, JL;Morrison, G;Wilson, RH
目的研究17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17-AAG）的临床毒性，观察17-AAG在6个剂量水平（10 ~ 56 mg/m2）下的临床毒性。通过高效液相色谱法测定17-AAG的药物水平。通过免疫印迹分析外周血单个核细胞裂解液中靶蛋白含量的变化来监测17-AAG的生物学效应。结果17-AAG的毒性在剂量高达28 mg/m2时是可接受的。由于第二次发生2级肝转氨酶炎，队列扩大到3例40 mg/m2的患者。接受56 mg/m2治疗的6例可评估患者中有2例出现可逆的3级肝转氨酶炎。另外5名患者以40 mg/m2的剂量入组;无剂量限制性毒性。40和56 μ g/M2时17-AAG的最大血浆浓度（C-max）分别为1，724和2，046 ng/mL;平均血浆暴露（AUC）分别为2，809和6，708小时（.）ng/mL。不到3%的日剂量经尿液排泄。清除率与体表面积无关。14 Mg/M2剂量的17-AAG可明显增加葡萄糖相关的78 kd蛋白或热休克蛋白70的蛋白含量，而>= 28 mg/m2剂量的17-AAG可明显降低Lck或Baf 1的蛋白含量，提示17-AAG可能具有生物活性。
Purpose To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks.Patients and Methods Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells.Results Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C-max) of 17-AAG at 40 and 56 Mg/M2 were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours(.)ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with 14 Mg/M2 and decreased protein content of either Lck or Baf1 with >= 28 mg/m(2) of 17-AAG.Conclusion 17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.