A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer
A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer
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DOI：
10.1158/1078-0432.ccr-06-1015
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发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
Erlichman, Charles
中科院分区：
文献类型：
--
作者：
Nowakowski, Grzegorz S.;McCollum, Andrea K.;Erlichman, Charles
目的：为了确定17-烯丙基氨基-去甲氧基-格尔德霉素（17-AAG）的最大耐受剂量（MTD）、剂量限制性毒性和药代动力学，每21天在第1、4、8和11天给药，并检查17-AAG对伴侣蛋白和客户蛋白水平的影响。通过标准标准评价毒性和肿瘤反应。药代动力学和目标蛋白的水平进行了测量在不同的时间点在cycle one.Results：13例患者入组研究。MTD定义为220 mg/m2。剂量限制性毒性如下：脱水、腹泻、高血糖症和肝毒性。在MTD时，17-AAG的平均清除率为18.7 L/h/m（2）。在第1天输注后6小时，外周血单核细胞中整合素相关激酶显著降低，但在25小时时未降低。在第1天用17-AAG处理显著增加了第4天热休克蛋白（HSP）70的预处理水平，这与应激反应的诱导一致。体外诱导应激反应和上调HSP 70导致A549细胞对HSP 90靶向治疗的抗性增加。结论：每周两次给药的17-AAG的MTD为220 mg/m2。在该剂量水平下的处理导致靶蛋白的显著变化，并且还导致HSP 70的延长增加。这增加了HSP 70诱导作为应激反应的一部分可能有助于抵抗17-AAG的可能性。
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins.Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one.Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m(2). Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m(2). There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells.Conclusions: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m(2). Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.