Evaluation of plasma insulin-like growth factor binding protein 2 and Her-2 extracellular domain as biomarkers for 17-allylamino-17-demethoxygeldanamycin treatment of adult patients with advanced solid tumors
Evaluation of plasma insulin-like growth factor binding protein 2 and Her-2 extracellular domain as biomarkers for 17-allylamino-17-demethoxygeldanamycin treatment of adult patients with advanced solid tumors
复制标题
DOI：
10.1158/1078-0432.ccr-06-2286
复制
发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Egorin, Merrill J.
中科院分区：
文献类型：
--
作者：
Eiseman, Julie L.;Guo, Jianxia;Egorin, Merrill J.
目的：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的相互作用导致许多蛋白质（包括Her-2-neu）的蛋白酶体降解，随后降低胰岛素样生长因子结合蛋白-2（IGFBP-2）的表达。携带BT474人乳腺癌异种移植物的小鼠血清中IGFBP-2和Her-2胞外结构域（Her-2 ECD）的浓度在17-AAG处理后降低。我们调查这种现象是否发生在患者身上。材料与方法：在0 - 72小时之间，从27名接受17-AAG单药治疗的患者（剂量在10 - 307 mg/m2之间）和18名接受17-AAG单药治疗的患者（剂量在220 - 450 mg/m2之间）以及18名接受70 - 75 mg/m2氯塞鲁肽联合治疗的患者中采集了8 - 15份血浆样本。还从12名健康志愿者中获得了治疗前血浆样本。结果：患者治疗前血浆IGFBP-2浓度（171 ± 116 ng/mL）是健康志愿者（85 ± 44 ng/mL）的2倍，差异有统计学意义（P < 0.05）。17-AAG处理后，血浆IGFBP-2和Her-2 ECD浓度无一致的剂量依赖性或时间依赖性变化。IGFBP-2浓度在8例患者中下降>= 40%，在8例患者中增加2- 5倍，在29例患者中基本保持不变。Her-2 ECD浓度下降>= 40%，在10例患者中，增加1.5- 5倍，在2例患者中，并保持基本不变，在25 patients.Conclusions：如前所述，IGFBP-2浓度在癌症患者的血浆中显着高于那些在健康志愿者。与小鼠模型相反，17-AAG治疗与患者血浆中IGFBP-2或Her-2 ECD浓度的降低不一致。
Purpose: 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.Materials and Methods: 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 clocetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA.Results: 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 >= 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 >= 40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients.Conclusions: 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.