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

• Published in: Gan to kagaku ryoho Vol. 15; no. 11; p. 3109
• Main Authors: Nishiyama, M, Takagami, S, Kim, R, Kirihara, Y, Saeki, T, Jinushi, K, Niimoto, M, Hattori, T
• Format: Journal Article
• Language: Japanese
• Published: Japan 01.11.1988
• Subjects: 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
• ISSN: 0385-0684

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.