Resolution of the function of cancer cells and the application for tailor-made therapy using bio-simulation analysis

代谢组分析技术近年来有了很大的发展，不仅应用于细菌和植物的研究，而且还应用于包括癌症科学在内的临床和药物疗效研究。在可用于代谢组分析的各种分析方法中，我们特别选择了毛细管电泳质谱(CE-MS)，并建立了一种基于CE-MS的方法来综合分析带电的低分子化合物。CE-MS代谢组分析针对糖酵解、戊糖磷酸途径、TCA和尿素循环以及参与氨基酸、多胺、嘌呤和嘧啶代谢的中间体，因此最适合于表征细胞能量代谢的代谢物的综合定量。同时，药物敏感性的研究主要通过基因组学和转录组学方法进行；然而，很少有研究对化合物a…进行代谢组规模的分析。根据细胞代谢的时程变化，检测药物敏感性。因此，为了阐明吉西他滨对癌细胞代谢的影响，并阐明其可能的耐药机制，我们对吉西他滨作用后的胰腺癌细胞株PANC-1进行了时程代谢组分析。通过使用CE-MS对吉西他滨处理的PANC-1中239种代谢物的时间变化进行量化，我们既观察到了以嘧啶代谢物为主的预测波动，也观察到了诸如TCA中间体、氨基酸和嘌呤代谢物显著增加等意想不到的变化。我们将在未来利用比较代谢组学的方法，利用耐药株和敏感株来阐明细胞对吉西他滨的耐药机制。此外，我们的目的是通过分析血液和尿样的代谢组来预测化疗过程中耐药特性的变化。此外，我们还将研究多药给药对代谢的影响以及与副作用相关的代谢变化，这在单一药物治疗下是观察不到的。因此，我们将有助于在基于代谢组分析的个体化治疗中建立一种易于使用的方法。较少

Metabolome analysis technology has been dramatically improved in recent years and applied not only to the research in bacteria and plants but also to clinical and drug efficacy studies including cancer science. Among various analytical methods available for metabolome analysis, we particularly selected capillary electrophoresis mass spectrometry (CE-MS) and established a CE-MS-based method to comprehensively analyze charged, low-molecular-weight compounds. Metabolome analysis by CE-MS targets the compounds involved in glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and the intermediates involved in amino acid, polyamine, purine, and pyrimidine metabolisms, and thus, is best-suited for the integrative quantification of metabolites that characterize the energy metabolism of cells. Meanwhile, research in drug sensitivity has been conducted mainly by applying genomics and transcriptomics approaches; however, few studies conducted metabolome-scale analysis of compounds a … More nd examined the property of drug sensitivity based on the time-change of cell metabolism. Accordingly, in order to elucidate the effect of gemcitabine on the metabolism of cancer cells and clarify the potential drug resistance mechanisms, we conducted time-course metabolome analysis of Panc-1 (a pancreatic cancer cell line) after the treatment with gemcitabine. As a result of quantifying the time-change of 239 metabolites in gemcitabine-treated Panc-1 by using CE-MS, we observed both predicted fluctuations primarily in the pyrimidine metabolites and unexpected changes such as the significant increase of TCA intermediates, amino acids, and purine metabolites. We will attempt to elucidate the resistance mechanism of cells against gemcitabine using the drug-resistant and sensitive strains by exploiting a comparative metabolomics approach in future. Moreover, we aim to predict the change in drug resistance property in the course of chemotherapy treatment by profiling the metabolome of blood and urine samples. Furthermore, we will also investigate the effects of multidrug administrations on the metabolism and the metabolic changes associated with side effects, which cannot be observed under a single drug treatment. We will thus contribute to the establishment of an easy-to-use approach in individualized therapy based on metabolome analysis. Less