[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.
D000284:Administration, Oral; D000818:Animals; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003857:Deoxyuridine / Q000008:administration & dosage; D050744:Dihydrouracil Dehydrogenase (NAD+); D004357:Drug Synergism; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011743:Pyrimidines / Q000096:biosynthesis*; D012517:Sarcoma, Yoshida / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D005641:Tegafur / Q000008:administration & dosage*; D013936:Thymidine / Q000008:administration & dosage; D013941:Thymine / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage*; D014529:Uridine / Q000008:administration & dosage
D004273:DNA, Neoplasm; D011743:Pyrimidines; D005641:Tegafur; D014498:Uracil; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050744:Dihydrouracil Dehydrogenase (NAD+); D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; C030986:pyrimidine; D013941:Thymine; D005472:Fluorouracil; D013936:Thymidine; D003857:Deoxyuridine; D014529:Uridine