[Inhibition of thymidylate synthetase and antiproliferative effect by 1-hexylcarbamoyl-5-fluorouracil]

Gan To Kagaku Ryoho. 1988 Nov;15(11):3109-13.
[Article in Japanese]

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / pathology
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / pathology
  • Thymidylate Synthase / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Thymidylate Synthase
  • carmofur
  • Fluorouracil