title: [Inhibition of thymidylate synthetase and antiproliferative effect by 1-hexylcarbamoyl-5-fluorouracil].
abstract: In order to estimate tumor chemosensitivity of fluoropyrimidine derivative, inhibition of thymidylate synthetase (TS) was investigated using a nude mouse experimental system. Four human tumors xenografted in nude mice; H-111, SH-8 and SH-10, each established from gastric cancer, and EH-1 from esophageal cancer, were used. When the transplanted tumor volumes reached to approximately 200 mm3, 1-hexylcarbamoyl-5-fluorouracil (HCFU) was given for 5 days. Tumors was removed for the measurement of total and free TS at 0 hr, 6 hrs and 24 hrs after the last administrations. Simultaneously, the anti-proliferative effects were investigated according to the therapeutic protocol of NCI. No positive correlation between the inhibition rate of TS and the anti-proliferative effects was observed, although the absolute values of free TS were similar to the tumor inhibition rates. The measurement of total TS provided a highest concentration in SH-8, while extremely low in EH-1. On the analysis of free TS, a significant increase of the concentration was observed at 24 hrs after the last administration compared with at 6 hrs in SH-8. These results indicate that free TS had a potentiality as a new parameter for predicting tumor chemosensitivity of fluoropyrimidine derivative and the analysis of TS should be affected strongly by the characteristics of enzymic activity of examined tumor.
authors.affiliation: Dept. of Surgery, Research Institute for Nuclear Medicine and Biology, Hiroshima University.
authors.forename: M
authors.initials: M
authors.lastname: Nishiyama
authors.forename: S
authors.initials: S
authors.lastname: Takagami
authors.forename: R
authors.initials: R
authors.lastname: Kim
authors.forename: Y
authors.initials: Y
authors.lastname: Kirihara
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: K
authors.initials: K
authors.lastname: Jinushi
authors.forename: M
authors.initials: M
authors.lastname: Niimoto
authors.forename: T
authors.initials: T
authors.lastname: Hattori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D013940:Thymidylate Synthase; C017367:carmofur; D005472:Fluorouracil