Proteomic approach for personalized Medicine in cancer chemotherapy

为了提高肿瘤化疗水平，迫切需要根据肿瘤个体化特点进行个体化用药。可以预测化疗敏感性的有用的生物标志物有望成为为每个患者选择最佳治疗方案的有力工具之一。结直肠癌是一种常见的致命性疾病，而奥沙利铂(L-OHP)、伊立替康(CPT-11)和氟尿嘧啶(5-FU)是治疗结直肠癌的关键药物。我们的目标是通过蛋白质组学和代谢组学的方法发现有用的生物标志物来预测化疗的敏感性。L-OHP敏感性生物标志物的发现：采用11种不同类型的人结肠癌细胞株，以IC50值为评价指标评价奥沙利铂的敏感性，并用表面增强激光解吸电离飞行时间质谱仪分析其细胞内蛋白质表达谱。奥沙利铂敏感性与…的表达差异映射分析及线性回归分析结论：1.根据检测到的每个肿块的峰值强度，我们发现了一个预测L-OHP敏感性的潜在蛋白质生物标志物，其表达与L-OHP的敏感性有很好的相关性。CPT-11敏感性生物标志物的发现：为了阐明癌细胞对CPT-11的敏感性，将低敏感性(HT-29)和高敏感性(HCT-116)的人结直肠癌移植到裸鼠皮下，用毛细管电泳联用飞行时间质谱仪(CE-TOFMS)分析其血清。在血清代谢产物中检测到低敏感性和高敏感性癌细胞之间的特征峰。它可能是一个有用的生物标志物，可以揭示癌症对CPT-11治疗的敏感性。癌细胞对5-FU的代谢反应性：人结直肠癌LS174T细胞暴露于高(100μM)或低(2μM)5-FU浓度。染毒0、4、8、12h后，提取细胞内代谢物，进行CE-TOFMS分析。我们首次展示了5-FU暴露后细胞内代谢产物通量的动态变化。较少

To improve cancer chemotherapy, personalized medicine based on the individual tumor characteristics is urgently needed. Useful biomarkers that can predict the chemosensitivity is expected to be one of the strong tools to select the optimal treatment for each patient. Colorectal cancer is a common and lethal disease, and oxaliplatin (L-OHP), irinotecan (CPT-11) and fluorouracil (5-FU)are key drugs in the treatments for colorectal cancer. We aimed to discover useful biomarkers for predicting the sensitivity to chemotherapy by proteomic and metabolomic approach.1. Discovery of biomarkers for L-OHP sensitivity: Using various types of 11 human colorectal cancer cell lines, we evaluated the oxaliplatin sensitivity as IC50 values, and analyzed their intracellular protein expression profiles by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). By Expression Difference Mapping analysis and linear regression analysis between oxaliplatin sensitivity and … More the peak intensity of each mass detected, we found a potential protein biomarker for predicting L-OHP sensitivity which expression is well associated with L-OHP sensitivity.2. Discovery of biomarkers for CPT-11 sensitivity: To elucidate the responsiveness of cancer cells to CPT-11, human colorectal carcinoma with low sensitivity(HT-29)or high sensitivity (HCT-116) was implanted subcutaneously into nude mice, and their serum was analyzed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). A characteristic peak was detected between low sensitivity and high sensitivity cancer cells in the serum metabolites. It might be a useful biomarker that can reveal sensitivity of cancer to CPT-11 therapy.3. The metabolic responsiveness of cancer cells to 5-FU exposure: Human colorectal carcinoma LS174T cells were exposed to high (100 μM) or low (2 μM) 5-FU concentration. After 0, 4, 8, and 12 h exposure, all intracellular metabolites were extracted and analyzed by CE-TOFMS. We firstly showed the dynamics of intracellular metabolites flux after 5-FU exposure. Less