McClelland C M, Gullick W J
Cancer Biology Laboratory, Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
Br J Cancer. 2007 Jan 29;96(2):284-9. doi: 10.1038/sj.bjc.6603544. Epub 2007 Jan 9.
Epidermal growth factor receptor is a potential target for cancer treatment and new small-molecule tyrosine kinase inhibitor drugs have been designed to inhibit its activity. In this work we identify potential surrogate markers of drug activity using a proteomic analysis. Two-dimensional electrophoresis was optimised to compare expression patterns of proteins secreted from the cancer cell lines A431 and A549 treated with Gefitinib (Iressa) vs untreated or vehicle-only-treated samples. Upregulated or downregulated proteins were detected using Phoretix 2D image analysis software. Several proteins were then identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. In one case, upregulation of Protein Disulphide Isomerase in response to Gefitinib was confirmed by Western blot analysis, and the response was shown to be concentration dependent. The identification of surrogate markers may be of use for the evaluation of new drugs, in preclinical models, in clinical trials and in the therapy of individual patients to give optimal biological drug doses.
表皮生长因子受体是癌症治疗的一个潜在靶点，新型小分子酪氨酸激酶抑制剂药物已被设计用于抑制其活性。在这项工作中，我们使用蛋白质组学分析来确定药物活性的潜在替代标志物。优化二维电泳以比较用吉非替尼（易瑞沙）处理的癌细胞系A431和A549分泌的蛋白质的表达模式，与未处理或仅用溶剂处理的样品进行比较。使用Phoretix 2D图像分析软件检测上调或下调的蛋白质。然后使用基质辅助激光解吸/电离飞行时间（MALDI-TOF）质谱法鉴定了几种蛋白质。在一个案例中，通过蛋白质免疫印迹分析证实了蛋白质二硫键异构酶对吉非替尼的上调反应，并且该反应显示为浓度依赖性。替代标志物的鉴定可能有助于在临床前模型、临床试验以及个体患者的治疗中评估新药，以给予最佳的生物药物剂量。
