| Co-Investigator(Kenkyū-buntansha) |
EGAWA Shinichi Tohoku University, School of Medicine Department of Surgery, Associate Professor (00270679)
FUKUYAMA Shoji Tohoku University, Hospital Department of Surgery, Assistant Professor (10344673)
MOTOI Fuyuhiko Tohoku University, Hospital Department of Surgery, Assistant Professor (30343057)
HORII Akira Tohoku University, Department of School of Medicine Molecular Pathology, Professor (40249983)
SOGA Tomoyoshi Keio University, Institute for Advanced Biosciences, Professor (60338217)
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| Budget Amount *help |
¥16,860,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2007: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2006: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Research Abstract |
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
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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
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