Schedule-dependent inhibition of thymidylate synthase by 5-fluorouracil in gastric cancer.
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/m2 for 48 hours) or as a bolus injection (500 mg/m2 x 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 +/- 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.
Tsujinaka
T
T
Department of Surgery II, Osaka University Medical School, Japan.
Kido
Y
Y
Shiozaki
H
H
Iijima
S
S
Homma
T
T
Sakaue
M
M
Mori
T
T
D000368:Aged; D000818:Animals; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics; D004334:Drug Administration Schedule; D004355:Drug Stability; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008198:Lymph Nodes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011003:Ploidies; D012510:Sarcoma 180 / Q000188:drug therapy / Q000201:enzymology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000601:surgery; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D004273:DNA, Neoplasm; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D005472:Fluorouracil