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Uracil prevented the growth inhibition of Staphylococcus aureus 209P by 5fluorouracil (5-FU). However, uracil did not reverse the growth inhibition by 5-FU in mammalian FM3A/B and HeLa cells even at 1,000 times the concentration of 5-FU. These findings suggested that co-administration of uracil or its derivatives with 5-FU or the 5-FU derivative, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), might prevent the degradation of 5-FU released from FT207 and thus increase the antitumor activity of FT-207. It was found that the antitumor activity of FT-207 on sarcoma-180 and AH-130 tumor was enhanced by oral administration of uracil, dUrd, or Urd. This enhancement of the antitumor activity of FT-207 increased with the dose of uracil. Uracil caused more enhancement than did dUrd or Urd. The correlation between the doses of FT-207 and uracil, and the 5-FU levels in the tumor and blood was studied. When appropriate dose of uracil was co-administered with 3H-FT-207, 5-FU levels in the tumor became much higher than when FT-207 was administered alone and reduced very slowly, while that in the blood rapidly decreased. Consequently, the ratio of 5-FU level in the tumor to that in the blood increased markedly. Co-administration of 5-FU and uracil increased the 5-FU levels in the blood and tumor to almost the same extent and the ratio of these levels was less than that after administration of 5-FU. These findings suggest that, in contrast to the results with FT-207, co-administration of uracil with 5-FU increased its antitumor activity and also the toxicity of 5-FU.

Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil.