Mechanisms of potentiation of antitumor activity of 5-fluorouracil by ribothymidine in a mouse tumor system.
In the presence of ribothymidine, the uptake of 5-fluorouracil (5-FU) was enhanced in Ehrlich ascites carcinoma cells in vitro, and was efficiently converted to FU-nucleotides. In these cells, almost all ribothymidine was found to be converted to thymine by, presumably, uridine phosphorylase. The enhanced uptake of 5-FU and its efficient conversion to FU-nucleotides were also observed in Ehrlich ascites carcinoma of ribothymidine-coadministered mice. The radioactivity of 5-FU-14C in the carcinoma cells, which was detected mainly in the acid-soluble fraction immediately after the administration and then shifted to the ribonucleic acid fraction, was approximately 2-fold higher in the ribothymidine-coadministered group than in the control group. On the other hand, ribothymidine-14C was also taken up by the carcinoma cells and an appreciable portion of its radioactivity appeared in the thymine fraction. Thymine produced from ribothymidine-14C was also detected in the extracellular ascitic fluid. The conversion of ribothymidine to thymine was assumed to be catalyzed by uridine phosphorylase, suggesting that ribose 1-phosphate was coproduced and served as a ribose donor for 5-FU. These results suggest that ribothymidine may act as a ribose donor for 5-FU to form FU-nucleotides via 5-fluorouridine in carcinoma cells, resulting in the potentiation of 5-FU activity.
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014541:Uridine Kinase / Q000032:analysis; D014543:Uridine Phosphorylase / Q000032:analysis
C009182:ribothymidine; D014543:Uridine Phosphorylase; D014541:Uridine Kinase; D005472:Fluorouracil; D014529:Uridine