Antitumor Activity of BOF‐A2, a New 5‐Fluorouracil Derivative

A compound containing both CNDP (3‐cyano‐2,6‐dihydroxypyridine), an inhibitor of 5‐fluorouracil (5‐FU) degradation, and EM‐FU (1‐ethoxymethyl‐5‐fluorouracil), a masked form of 5‐FU, was synthesized and named BOF‐A2 (3‐[3‐(6‐benzoyloxy‐3‐cyano‐2‐pyridyloxycarbonyl)benzoyl]‐1‐ethoxymethyl‐5‐fluorouracil). The antitumor activity of BOF‐A2 was investigated in sarcoma‐180‐bearing mice and Yoshida sarcoma‐bearing rats. The ED 50 (the dose for 50% inhibition) values of BOF‐A2 were 25 mg/kg against sarcoma‐180 and 15 mg/kg against Yoshida sarcoma. In vitro studies showed that BOF‐A2 was rapidly degraded to EM‐FU and CNDP in homogenates of the liver and small intestine of mice and rats, and in sera of mice, rats and human, and the conversion of EM‐FU to 5‐FU occurred only in the microsomal fraction of rat liver in the presence of NADPH. After oral administration of BOF‐A2 at 15 mg/kg to Yoshida sarcoma‐bearing rats, BOF‐A2 was hydrolyzed to EM‐FU, CNDP and 5‐FU, and their maximum concentrations in the blood were 2000 ng/ml, 300 ng/ml and 40 ng/ml, respectively. Moreover when BOF‐A2 was given at the same dose to tumor‐bearing mice and rats, the 5‐FU levels in the tumor tissue increased much more than those in the blood and persisted for more than 8 h, whereas those in the blood decreased more rapidly. This accumulation and maintenance of a high level of 5‐FU in the tumor tissue are concluded to be related to the high antitumor activity of BOF‐A2.