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-ethoxy methyl-
5- fluorouracil). The antitumor activity of
BOF-A2 was investigated in sarcoma-180-bearing mice and
Yoshida sarcoma-bearing rats. The ED50 (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.