Selective protection by uridine of growth inhibition by 5-fluorouracil (5FU) mediated by 5FU incorporation into RNA, but not the thymidylate synthase mediated growth inhibition by 5FU-leucovorin.
Fluorouracil (5FU) acts by RNA-incorporation and inhibition of thymidylate synthase; the first action is counteracted by uridine, and the second is enhanced by leucovorin (LV). Growth inhibition of C26-10 colon cancer cells by 5FU was enhanced by LV and rescued by uridine, but 5FU-LV was only partially rescued by uridine. In WiDr cells, 5FU sensitivity was not enhanced by LV, while both 5FU and 5FU-LV were rescued by uridine. Intermediate trends were found in SW948 and HT29 cells. Uridine rescue in mice allowed 1.5-fold increase in 5FU dose, leading to 2-fold increase in the antitumor effect and thymidylate synthase inhibition in resistant Colon-26 tumors. In the sensitive Colon-26-10 tumor, uridine rescue decreased 5FU-RNA incorporation > 10-fold, without affecting the antitumor activity. The use of LV and uridine can differentiate between two mechanisms of action of 5FU.
Codacci-Pisanelli
G
G
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Noordhuis
P
P
van der Wilt
C L
CL
Peters
G J
GJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D051379:Mice; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects; D012680:Sensitivity and Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014529:Uridine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012313:RNA; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; D014529:Uridine