Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-emethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers
Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-emethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers
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DOI：
10.1158/1078-0432.ccr-04-2322
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发表时间：
2005-05-01
影响因子：
11.5
通讯作者：
Egorin, MJ
中科院分区：
文献类型：
--
作者：
Ramanathan, RK;Trump, DL;Egorin, MJ
目的：17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17 AAG）是一种苯醌类抗生素，通过特异性结合热休克蛋白90（HSP 90）下调癌蛋白。我们进行了17 AAG的I期研究，以建立剂量限制性毒性和最大耐受剂量，并表征17 AAG的药代动力学和药效学。实验设计：在1或2小时内静脉内给予递增剂量的17 AAG，每周一次，每4周一次，给3至6名患者的队列。采用高效液相色谱法测定17-氨基-17-去甲氧基格尔德霉素（17-amino-17-demethoxygeldanamycin，17 AG）和17-氨基-17-去甲氧基格尔德霉素（17-amino-17-demethoxygeldanamycin，17 AG）的血浆药动学。Western blot检测外周血单个核细胞中HSP 70和HSP 90的表达。最大耐受剂量为295 mg/m2。在接受395 mg/m2治疗的两名患者中均发生了剂量限制性毒性（3级胰腺炎和3级疲劳）（2）。常见的药物相关毒性（1级和2级）为疲乏、厌食、腹泻、恶心和呕吐。29.5%的患者发生可逆性肝酶升高。血液学毒性极轻微。未观察到客观反应。17 AAG药代动力学呈线性。17 AAG的主要活性代谢物17 AG的血浆峰浓度和曲线下面积随17 AAG剂量增加而增加，但其关系比17 AAG更多变。血浆中的17 AAG和17 AG> 90%蛋白结合。外周血单个核细胞HSP 90和HSP 70含量无一致性变化。结论：17 AAG剂量在10 ~ 295 mg/m2之间耐受性良好。17 AAG药代动力学呈线性。外周血单个核细胞HSP 90和HSP 70是无意义的药效学标志物。未来研究的推荐剂量为295 mg/m2，每周一次，每4周重复一次。
Purpose: 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.Experimental Design: 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.Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m(2). Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m(2). 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.Conclusions: 17AAG doses between 10 and 295 mg/m(2) 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.