Antitumor Activity of Fluoropyrimidines and Thymidylate Synthetase Inhibition

Experimental chemotherapy with 5‐fluorouracil (5‐FU; 60 mg/kg), l‐hexylcarbamoyl‐5‐fluorouracil (HCFU; 70 mg/kg), 3‐(3‐(6‐benzoyloxy‐3‐cyano‐2‐pyridyloxycarbonyI)benzoyl)‐l‐ethoxymethyl‐5‐fluorouracil (BOF‐A2; 30 mg/kg) and UFT (20 mg/kg as tegafur with uracil at a molar ratio of 1:4) was performed using human gastric (H‐111) and colon (Co‐4) carcinoma strains in nude mice. 5‐FU was administered ip with a q4d × 3 schedule and the other agents were given po daily for three weeks. Concentrations of 5‐FU in the serum and the tumor were assessed by gas chromatography‐ntass fragmentography, two hours or 12 days (5‐FU) after the last treatment, and thymidy late synthetase (TS) was assayed according to the method of Spears et al. using the same schedule. The antitumor activity of the agents was assessed in terms of the actual tumor weight at the end of the experiment. HCFU was effective against both strains and 5‐FU was effective against Co‐4, although the other agents were ineffective against either strain. Statistically significant correlations were found between the serum and tumor concentrations of 5‐FU and antitumor activity. Statistically significant correlations were also observed between the antitumor activity and TS inhibition rate (TSIR) and the activity of free thymidylate synthetase (TSfree), with higher TSIR and lower TSfree resulting in higher antitumor activity. Therefore, TSIR and TSfree were thought to be promising indicators for predicting the antitumor activity of fluoropyrimidines.