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To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5\u2010FU) metabolism were examined <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. TXT alone and in combination with 5\u2010FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK\u20101, and MKN\u20101, \u201028, \u201045 and \u201074), in a time\u2010 and dose\u2010dependent manner. Moreover, striking synergistic effects were observed in TMK\u20101 cells <jats:italic>in vitro<\/jats:italic> with IC<jats:sub>50<\/jats:sub> values of between 4.73 and 0.61 nM 5\u2010FU. Furthermore, in TMK\u20101 xenografts, 5\u2010FU\/TXT cotreatments exhibited synergistic antitumor effects. The combination of S\u20101 and TXT, however, exhibited greater growth\u2010inhibitory effects than the 5\u2010FU\/TXT cotreatments. The mechanisms underlying these synergistic effects of S\u20101 and TXT were examined by expression and activity analyses of the 5\u2010FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9\u2010fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S\u20101 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.21879","type":"journal-article","created":{"date-parts":[[2006,3,24]],"date-time":"2006-03-24T01:18:49Z","timestamp":1143163129000},"page":"783-791","source":"Crossref","is-referenced-by-count":67,"title":["Synergistic effects of docetaxel and S\u20101 by modulating the expression of metabolic enzymes of 5\u2010fluorouracil in human gastric cancer cell 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