Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism.
Exposure of L1210 leukemia cells first to 0.1 to 100 micromolar methotrexate and then to 10 micromolar 5-fluorouracil produces a synergistic effect on the number of cells killed in culture. Methotrexate dose-related increases occur in the concentrations of intracellular 5-fluorouracil ribonucleotides and 5-fluoro-2'-deoxyuridylate and in the incorporation of 5-fluorouracil into RNA. These increases are correlated with increased concentrations of intracellular phosphoribosylpyrophosphate. It is proposed that the enhanced formation of ribonucleotides of 5-fluorouracil and the subsequent incorporation of these compounds into RNA in methotrexate-treated cells may account for synergism between these agents.
D000818:Animals; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D007939:Leukemia L1210; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D012334:RNA, Neoplasm; D012265:Ribonucleotides; D010754:Phosphoribosyl Pyrophosphate; D013940:Thymidylate Synthase; D005472:Fluorouracil; D008727:Methotrexate