title: A potential important role for thymidylate synthetase inhibition on antitumor activity of fluoropyrimidine and raltitexed.
abstract: BACKGROUND
  Because thymidylate synthetase (TS) is a key enzyme in DNA synthesis, it has been used as a target for cancer chemotherapy.
  
  
  METHODS
  We investigated the combined antitumor activity of raltitexed, 5-FU and UFT on human tumor xenografts in nude mice and examined changes in TS activity and 5-FU-bound RNA (F-RNA) levels. Human gastric (SC-1-NU) or colon (HT-29) carcinoma xenografts were transplanted subcutaneously into nude mice, and drugs administered intraperitoneally (raltitexed and 5-FU) or perorally (UFT) daily for 5 days, and repeated once after a 2-day interval.
  
  
  RESULTS
  The antitumor effects were mostly equivalent between the treatment groups despite the different drugs and sequence orders. TS inhibition rates correlated with the tumor inhibition rate, which was statistically significant, while F-RNA levels did not correlate with antitumor activity.
  
  
  CONCLUSIONS
  Our results indicated that the combination of fluoropyrimidine-related agents should be directed towards increased TS inhibition rather than increased F-RNA levels.
authors.affiliation: Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kabeshima
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kubota
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saikawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishibori
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitajima
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology; D005641:Tegafur / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; D005641:Tegafur; D014498:Uracil; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil