Ramanathan Ramesh K, Trump Donald L, Eiseman Julie L, Belani Chandra P, Agarwala Sanjiv S, Zuhowski Eleanor G, Lan Jing, Potter Douglas M, Ivy S Percy, Ramalingam Sakkaraiappan, Brufsky Adam M, Wong Michael K K, Tutchko Susan, Egorin Merrill J
Molecular Therapeutics/Drug Discovery Program, Biostatistics Department, Graduate School of Public Health, and Biostatistics Facility, University of Pittsburgh Cancer Institute, PA 15232, USA.
Clin Cancer Res. 2005 May 1;11(9):3385-91. doi: 10.1158/1078-0432.CCR-04-2322.
17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics.
Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly x 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot.
Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content.
17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly x 3, repeated every 4 weeks.
17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17AAG）是一种苯醌类抗生素，通过特异性结合热休克蛋白90（HSP90）来下调癌蛋白。我们开展了一项17AAG的I期研究，以确定剂量限制性毒性和最大耐受剂量，并对17AAG的药代动力学和药效学进行表征。
以每4周为一个周期，每周1次，共3次，每次1或2小时静脉输注递增剂量的17AAG，每组3至6名患者。通过高效液相色谱法评估17AAG和17-（氨基）-17-去甲氧基格尔德霉素（17AG）的血浆药代动力学。通过蛋白质印迹法检测外周血单核细胞中HSP70和HSP90的表达。
45名患者入组，接受10至395mg/m²之间的11个剂量水平治疗。最大耐受剂量为295mg/m²。接受395mg/m²治疗的两名患者均出现了剂量限制性毒性（3级胰腺炎和3级疲劳）。常见的药物相关毒性（1级和2级）为疲劳、厌食、腹泻、恶心和呕吐。29.5%的患者出现肝酶可逆性升高。血液学毒性极小。未观察到客观缓解。17AAG的药代动力学呈线性。17AAG的活性主要代谢产物17AG的血浆峰浓度和曲线下面积随17AAG剂量增加而升高，但与17AAG相比，其关系更具变异性。血浆中的17AAG和17AG与蛋白的结合率>90%。外周血单核细胞中HSP90或HSP70含量没有一致的变化。
10至295mg/m²的17AAG剂量耐受性良好。17AAG的药代动力学呈线性。外周血单核细胞HSP90和HSP70是无信息价值的药效学标志物。推荐用于未来研究的剂量为每周1次，每次295mg/m²，共3次，每4周重复一次。
