title: Effects of combined administration of DPD-inhibitory oral fluoropyrimidine, S-1, plus paclitaxel on gene expressions of fluoropyrimidine metabolism-related enzymes in human gastric xenografts.
abstract: BACKGROUND
  S-1 is the most effective oral fluoropyrimidine derivative widely used for patients with gastric carcinoma in Japan. Although S-1 plus taxane has been a promising candidate as an effective chemotherapeutic regimen, the mechanisms of its additive or synergistic anticancer effects and changes in gene expression after the administration of these agents have not yet been fully elucidated.
  
  
  METHODS
  Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine anticancer effects and gene expressions of fluoropyrimidine metabolism-related enzymes including thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and uridine phosphorylase (UP). Nude mice were treated with S-1, paclitaxel, and their combination. After treatment, in vivo antitumor effects of S-1, paclitaxel alone, and their combination and the effects on gene expressions of enzymes involved in 5-fluorouracil metabolism were examined using the RT-PCR method.
  
  
  RESULTS
  The combined use of S-1 and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. While consistent upregulation of dThPase and DPD gene expression was exhibited after administration of S-1, no further increase of dThPase gene expression after combined use of S-1 with paclitaxel was observed. There was no increase in TS gene expression after the administration of either S-1 alone or paclitaxel alone.
  
  
  CONCLUSIONS
  These results provide some insight into the mechanism and/or rationale underlying the additive to synergistic effect of combined administration of S-1 and paclitaxel in gastric carcinoma.
authors.affiliation: Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. ysakurai@fujita-hu.ac.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Ikuo
authors.initials: I
authors.lastname: Yoshida
authors.forename: Shingo
authors.initials: S
authors.lastname: Kamoshida
authors.forename: Kazuki
authors.initials: K
authors.lastname: Inaba
authors.forename: Jun
authors.initials: J
authors.lastname: Isogaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Komori
authors.forename: Ichiro
authors.initials: I
authors.lastname: Uyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsutsumi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009962:Orotate Phosphoribosyltransferase / Q000187:drug effects; D010094:Oxonic Acid / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005641:Tegafur / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000187:drug effects; D013940:Thymidylate Synthase / Q000187:drug effects; D014543:Uridine Phosphorylase / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; D005472:Fluorouracil