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-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.
Fujii
S
S
Biwako Research Institute, Otsuka Pharmaceutical Co., Ltd., Shiga.
Fukushima
M
M
Shimamoto
Y
Y
Ohshimo
H
H
Imaoka
T
T
Shirasaka
T
T
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D012510:Sarcoma 180 / Q000188:drug therapy*; D012517:Sarcoma, Yoshida / Q000188:drug therapy*
D000970:Antineoplastic Agents; D011725:Pyridines; C053195:2,6-dihydroxy-3-cyanopyridine; C059823:1-ethoxymethyl-5-fluorouracil; C053194:Emitefur; D005472:Fluorouracil