Eiseman Julie L, Guo Jianxia, Ramanathan Ramesh K, Belani Chandra P, Solit David B, Scher Howard I, Ivy S Percy, Zuhowski Eleanor G, Egorin Merrill J
Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213-1863, USA.
Clin Cancer Res. 2007 Apr 1;13(7):2121-7. doi: 10.1158/1078-0432.CCR-06-2286.
Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 human breast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients.
Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m(2) and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m(2) combined with 70 to 75 mg/m(2) of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA.
Pretreatment plasma IGFBP-2 concentrations in patients (171 +/- 116 ng/mL) were 2-fold higher than those in healthy volunteers (85 +/- 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by >or=40% in 8 patients, increased 2- to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by >or=40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients.
As previously reported, IGFBP-2 concentrations in plasma of cancer patients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）与热休克蛋白90相互作用会导致包括Her-2-neu在内的许多蛋白质被蛋白酶体降解，随后胰岛素样生长因子结合蛋白-2（IGFBP-2）的表达降低。携带BT474人乳腺癌异种移植瘤的小鼠血清中IGFBP-2和Her-2细胞外结构域（Her-2 ECD）的浓度在17-AAG治疗后会降低。我们研究了这种现象是否在患者中发生。
从27例接受10至307mg/m²单药17-AAG治疗的患者以及18例接受220至450mg/m² 17-AAG联合70至75mg/m²多西他赛治疗的患者中，在0至72小时内获取8至15份血浆样本。还从12名健康志愿者中获取了治疗前的血浆样本。通过酶联免疫吸附测定法（ELISA）对血浆IGFBP-2和Her-2 ECD浓度进行定量。
患者治疗前血浆IGFBP-2浓度（171±116ng/mL）比健康志愿者（85±44ng/mL；P<0.05）高2倍。17-AAG治疗后，血浆IGFBP-2和Her-2 ECD浓度没有一致的剂量依赖性或时间依赖性变化。8例患者的IGFBP-2浓度降低≥40%，8例患者升高2至5倍，29例患者基本保持不变。10例患者的Her-2 ECD浓度降低≥40%，2例患者升高1.5至5倍，25例患者基本保持不变。
如先前报道，癌症患者血浆中的IGFBP-2浓度显著高于健康志愿者。与小鼠模型不同，17-AAG治疗与患者血浆中IGFBP-2或Her-2 ECD浓度的降低没有持续相关性。
