[Regulation of enzyme activities involved in pyrimidine synthesis and its application to cancer chemotherapy].

We examined the enhancing effect of antitumor activity by co-administration of 5-FU or its masked form (FT-207) with bases or nucleosides of purine and pyrimidine. It was found that the antitumor activity of 5-FU or FT-207 on sarcoma-180 and AH-130 tumor was oral administration of uracil, deoxyuridine, uridine, thymine or thymidine. Uracil had more effect than other pyrimidine nucleotides in enhancing antitumor effect of these drug to FT-207 without toxicity. 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. On the ther hand, no enhancing antitumor activity of dRib-1-P, Rib-1-P, Ado, Xao, Guo, Ino, dAdo, dIno and dGuo to FT-207 was observed. Concentration of 5-FU in the tumor, blood and various organs of AH-130-bearing rats after oral administration of clinical doses of FT-270 and uracil was examined. 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. Moreover, it was found that 5-FU was mainly phosphorylated in the tumor tissues whereas it was mainly degraded in liver slices. Degradation of 5-FU in vitro was inhibited more by thymine than by uracil. Phosphorylation of 5-FU, however, was not inhibited by uracil, thymine or thymidine, even times the concentration of 5-FU. These findings suggest that the enhancement of antitumor activity of 5-FU-masked form is more important the inhibition of 5-FU degradation than the stimulation of 5-FU phosphorylation.