Goetz Matthew P, Toft David, Reid Joel, Ames Matthew, Stensgard Bridget, Safgren Stephanie, Adjei Araba A, Sloan Jeff, Atherton Pamela, Vasile Vlad, Salazaar Sandra, Adjei Alex, Croghan Gary, Erlichman Charles
Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
J Clin Oncol. 2005 Feb 20;23(6):1078-87. doi: 10.1200/JCO.2005.09.119.
We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity.
An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A53 and NQO12 genotypes were determined and correlated with pharmacokinetics and toxicity.
Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A53 and NQO12 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance.
The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.
我们确定了在28天周期的第1、8和15天对晚期实体瘤患者输注17-烯丙胺基-17-去甲氧基格尔德霉素（17-AAG）时的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。我们还对17-AAG的药代动力学、其对伴侣蛋白和客户蛋白的影响，以及细胞色素P450（CYP）3A5和NAD（P）H：醌氧化还原酶1（NQO1）基因多态性是否影响17-AAG的处置或毒性进行了表征。
采用加速滴定设计。在基线以及第1天和第15天对外周血单核细胞（PBMC）中的生物标志物进行测量，并在第1周期的第1天进行药代动力学分析。确定CYP3A53和NQO12基因型，并将其与药代动力学和毒性相关联。
21名患者在11个剂量水平接受了52个疗程的治疗。431mg/m²时的DLT为3级胆红素升高（n = 1）、谷草转氨酶升高（n = 1）、贫血（n = 1）、恶心（n = 1）、呕吐（n = 1）和肌痛（n = 1）。未观察到肿瘤反应。17-AAG持续增加PBMC中的热休克蛋白（Hsp）70水平。在MTD时，17-AAG的清除率和半衰期（t1/2）分别为11.6L/h/m²和4.15小时；而活性代谢物17-氨基格尔德霉素的t1/2为7.63小时。CYP3A53和NQO12基因多态性与17-AAG毒性无关。CYP3A5*3基因多态性与较高的17-AAG清除率相关。
每周一次的17-AAG的MTD为308mg/m²。17-AAG在PBMC中诱导Hsp70，表明Hsp90受到影响。正在使用每周两次的方案对17-AAG进行进一步评估，并且正在测试17-AAG与化疗联合的这种给药方案。
