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Schedule‐dependent inhibition of thymidylate synthase by 5‐fluorouracil in gastric cancer
Author(s) -
Tsujinaka Toshimasa,
Kido Yoshihiro,
Shiozaki Hitoshi,
Iijima Shohei,
Homma Taro,
Sakaue Masamori,
Mori Takesada
Publication year - 1992
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(19921215)70:12<2761::aid-cncr2820701206>3.0.co;2-f
Subject(s) - thymidylate synthase , medicine , bolus (digestion) , lymph , fluorouracil , gastroenterology , cancer , gastric mucosa , stomach , urology , pathology
Background . An optimal treatment schedule of 5‐fluorouracil (5‐FU) remains to be clarified. Methods . A randomized study was conducted to investigate schedule‐dependent thymidylate synthase (TS) inhibition by 5‐FU in 16 patients with gastric cancer who underwent surgical resection. Surgical specimens of tumor, normal gastric mucosa, and regional lymph nodes were obtained 12 hours after administration of 5‐FU either as a continuous infusion (1000 mg/m 2 for 48 hours) or as a bolus injection (500 mg/m 2 × 2 in 48 hours). Results . The total TS activity (567.8 ± 294 fmol/mg protein) and the rate of TS inhibition (74.7 ± 23.1%) in cancer tissues were significantly higher in the continuous‐infusion group than in the bolus‐injection group (228.5 ± 104.6 fmol/mg protein and 48.8 ± 12%, respectively). Likewise, the total TS activity (807.4 ± 440.3 fmol/mg protein) and the rates of TS inhibition in lymph nodes (72.3 t 17.1%) and in normal gastric mucosa (85.1 ± 12.2%) were significantly higher in the continuous‐infusion group than those in the bolus‐injection group (232.4 ± 142.3 fmol/mg protein and 53.6 ± 17.0% in lymph nodes and 46.5 ± 14.3% in normal gastric mucosa, respectively). There was a significant correlation between the total TS activity and TS inhibition. Conclusions . Continuous infusion of 5‐FU provides a superior antimetabolic effect in the treatment of gastric cancer, which may lead to a superior antitumor effect.