brivudine and doxifluridine

The antitumor activity of 5'-deoxy-5-fluorouridine (DFUR), a prodrug of 5-fluorouracil (5-FU), is markedly enhanced if DFUR treatment is combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). Combined oral administration of DFUR (10 mg/kg) and BVDU (10 mg/kg) three times (every 3 h) per day for 5 days afforded greater antitumor activity than a single dose of DFUR (300 mg/kg/day) for 5 days in mice bearing either adenocarcinoma 755 or Lewis lung carcinoma, while in the colon 26 system the antitumor effects of both treatment regimens were equivalent. Thus, a low-dose regimen of DFUR when combined with BVDU provides a similar or greater antitumor activity than a high-dose regimen of DFUR that is not combined with BVDU. The area under the curve of plasma 5-FU following a treatment with the combination of DFUR (10 mg/kg) and BVDU (10 mg/kg) was equal to that following DFUR (300 mg/kg) treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Colonic Neoplasms; Drug Therapy, Combination; Floxuridine; Fluorouracil; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Pentosyltransferases; Prodrugs; Pyrimidine Phosphorylases

5'-Deoxy-5-fluorouridine (DFUR), whether or not combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was pursued in BDF1 mice from both a pharmacokinetic viewpoint, following a single oral dose administration, and an anticancer viewpoint, following 5 daily oral doses in mice inoculated subcutaneously with adenocarcinoma 755 tumor cells. Half-life (t1/2) values for the elimination of DFUR and 5-fluorouracil (5-FU) from plasma following DFUR (100 mg/kg) administration were about 0.80 and 0.39 hr, respectively. Plasma 5-FU AUC (area under the curve) values following oral DFUR (100 mg/kg) was 0.224 micrograms.hr/ml. If DFUR (100 mg/kg) was combined with BVDU (10 mg/kg) the t1/2 and AUC values for 5-FU increased from 0.39 to 1.24 hr, and from 0.224 to 1.699 micrograms.hr/ml, respectively. Thus, BVDU significantly increased the plasma levels of 5-FU. It had no effect on the plasma levels of DFUR. At 100 mg/kg, DFUR did not show a significant antitumor activity. At 500 mg/kg it effected a 90% inhibition in tumor growth. When combined with BVDU (10 mg/kg), DFUR at 100, 200 and 300 mg/kg reduced tumor growth by 96, 100 and 100%, respectively. The antitumor activity achieved by DFUR, in the presence or absence of BVDU, correlated highly significantly with the AUC values for plasma 5-FU.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bromodeoxyuridine; Chromatography, High Pressure Liquid; Drug Synergism; Floxuridine; Fluorouracil; Half-Life; Male; Mice; Neoplasm Transplantation; Spectrophotometry, Ultraviolet