Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents.
Concentration of 5-fluorouracil (5-FU) in the tumor, blood, and various organs of AH130-bearing rats after administration of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and uracil was examined. The concentration of 5-FU in blood was less than 0.02 microgram/ml with all combinations of FT-207 and uracil except high molar ratios of uracil to FT-207 (ratio, 5 and 10), whereas high concentrations of up to a maximum of 0.200 microgram/g on administration of uracil plus 5 or 7.5 mg/kg of FT-207 (ratio, 4), was found in the tumor. On oral administration of FT-207 plus uracil in various combinations, the highest T/B (ratio of concentration of 5-FU in the tumor to that in blood) value was obtained at a ratio of uracil to FT-207 of 4. With this combination, 5-FU concentration in the tumor, muscle, and spleen was higher than that after administration of FT-207 alone (5 mg/kg). These results suggest that at the clinical doses the optimum molar ratio of uracil to FT-207 is 4. Coadministration of cytosine enhanced the antitumor activity of FT-207 on sarcoma-180 in mice. However, cytosine enhanced the antitumor activity of FT-207 less than uracil and its coadministration resulted in a lower concentration of 5-FU in the tumor than coadministration of uracil.
D000284:Administration, Oral; D000818:Animals; D003596:Cytosine / Q000008:administration & dosage*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009374:Neoplasms, Experimental / Q000032:analysis / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D012510:Sarcoma 180 / Q000188:drug therapy / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage / Q000627:therapeutic use*; D014018:Tissue Distribution; D014498:Uracil / Q000008:administration & dosage*
D005641:Tegafur; D014498:Uracil; D003596:Cytosine; D005472:Fluorouracil