Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites sarcoma 180 tumor system.
The antitumor activity of 5-fluorouracil (FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine. The antitumor activity of FUra was significantly potentiated when guanosine was administered either 0 to 15 min before or 5 min after FUra. Changes in metabolites of FUra after potentiation by guanosine were investigated. Total radioactivity in the plasma was significantly decreased 10 min after the combined administration of [6-14C]FUra (3 mg/kg i.p.) and guanosine (100 mg/kg i.p.) in comparison with that of [6-14C]FUra alone and was slightly decreased by coadministration of [6-14C]FUra and adenosine. Conversely, it was significantly increased by uridine or cytidine. The decrease in total radioactivity in the plasma caused by guanosine was completely reversed by addition of cytidine. FUra, 5-fluorouridine, alpha-fluoro-beta-ureidopropionic acid, and alpha-fluoro-beta-alanine were found in the plasma. Intact FUra accounted for about 55% of the total radioactivity. The proportion of metabolites of [6-14C]FUra was not changed by coadministration of [6-14C]FUra and guanosine, adenosine, or cytidine, but the proportion of FUrd was increased by uridine. In the ascitic fluid, the total radioactivity derived from [6-14C]FUra was decreased by its combined administration with guanosine, and it was reversed by addition of cytidine. This pattern was similar to that in the plasma. The main FUra compound was intact FUra itself (90%), and 5-fluorouridine accounted for 1% of the total radioactivity in the ascitic fluid. On the other hand, total radioactivity of [6-14C]FUra in the tumor cells was significantly and slightly increased by guanosine and adenosine, respectively. Total radioactivity after [6-14C]FUra in combination with uridine or cytidine was less than that after [6-14C]FUra alone. Incorporation of [6-14C]FUra into RNA was increased about 3.7 times by its combination with guanosine in comparison with FUra alone, and it was increased 2.0, 0.6, and 0.7 times by adenosine, uridine, and cytidine, respectively. Moreover, FUra-nucleotides were significantly increased by guanosine. The increased radioactivity in RNA and FUra-nucleotides of tumor cells caused by guanosine was completely reversed by cytidine. These changes in incorporation into tumor cells were comparable to those in antitumor activity against ascites Sarcoma 180. The potentiation of antitumor activity of FUra by guanosine was considered to be due to an increase in incorporation of FUra into FUra-nucleotides and RNA in the tumor cells.
D000241:Adenosine / Q000627:therapeutic use; D000818:Animals; D002250:Carbon Radioisotopes; D003562:Cytidine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D006151:Guanosine / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D012510:Sarcoma 180 / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014529:Uridine / Q000627:therapeutic use
D002250:Carbon Radioisotopes; D006151:Guanosine; D003562:Cytidine; D000241:Adenosine; D005472:Fluorouracil; D014529:Uridine