An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors
An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors
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DOI：
10.3109/13547500903261347
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发表时间：
2010-02-01
期刊：
影响因子：
2.6
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Dakappagari, Naveen;Neely, Laura;Zhang, Hong
Hsp 90抑制剂正在用于治疗癌症的多项人体临床试验中进行研究，所述癌症包括骨髓瘤、乳腺癌、前列腺癌、肺癌、黑色素瘤、胃肠道间质瘤和急性髓性白血病。Hsp 90抑制剂在临床中的药效学活性目前通过使用蛋白质印迹分析在外周血单核细胞中诱导Hsp 70来评估，该方法是费力的、半定量的并且难以在临床中实施。由于据报道Hsp 70由肿瘤细胞分泌并在癌症患者的血清中升高，因此血清Hsp 70已被评价为潜在更稳健、容易且可重复测量的Hsp 90抑制生物标志物，作为细胞溶质Hsp 70的替代物。开发了一种高灵敏度和特异性的电致发光ELISA来测量血清Hsp 70，并用于评价离体和异种移植样品中的Hsp 70水平。在离体研究中，在暴露于Hsp 90抑制剂后48和72小时之间观察到肿瘤细胞Hsp 70的最大分泌。在体内研究中，荷瘤小鼠接受BIIB 021给药后，观察到血清Hsp 70增加3-4倍。引人注目的是，分泌的Hsp 70可在移植有人类肿瘤的小鼠中检测到，但在未处理的小鼠中检测不到，表明直接源自移植的肿瘤。临床样本分析显示基线水平较低（2-15 ng/ml
Hsp90 inhibitors are under investigation in multiple human clinical trials for the treatment of cancers, including myeloma, breast cancer, prostate, lung, melanoma, gastrointestinal stromal tumour and acute myeloid leukaemia. The pharmacodynamic activity of Hsp90 inhibitors in the clinic is currently assessed by Hsp70 induction in peripheral blood mononuclear cells using Western blot analysis, a method that is laborious, semiquantitative and difficult to implement in the clinic. Since Hsp70 was reported to be secreted by tumour cells and elevated in sera of cancer patients, serum Hsp70 has been evaluated as a potentially more robust, easily and reproducibly measured biomarker of Hsp90 inhibition as an alternative to cytosolic Hsp70. A highly sensitive and specific electrochemiluminescent ELISA was developed to measure serum Hsp70 and employed to evaluate Hsp70 levels in both ex vivo and xenograft samples. In ex vivo studies, maximal secretion of Hsp70 by tumour cells was observed between 48 and 72 h after exposure to Hsp90 inhibitors. In in vivo studies a 3-4-fold increase in serum Hsp70 was observed following treatment with BIIB021 in tumour-bearing mice. Strikingly, secreted Hsp70 was detectable in mice transplanted with human tumours but not in naive mice indicating a direct origination from the transplanted tumours. Analysis of clinical samples revealed low baseline levels (2-15 ng ml