The interaction between fluoropyrimidines and methotrexate, and [4C]-formate incorporation into nucleic acids and protein.
Changes are reported in [14C]-formate incorporation into nucleic acids and protein of Ehrlich ascites tumor cells during exposure to methotrexate (MTX) and fluoropyrimidines. The rate of [14C]-formate incorporation into RNA, DNA, and protein in the presence of only MTX was inhibited by 82%, 91%, and 75% respectively, when compared with control rates. However, in the presence of 5-fluorodeoxyuridine (FdUrd) plus MTX, formate incorporation into RNA, DNA, and protein was inhibited by 67%, 85%, and 66%. Incubation of cells in vitro with [3H]-dihydrofolate (DHF) results in its rapid conversion to [3H]-tetrahydrofolate (THF). The THF/DHF ratio from the soluble fraction of cells that were incubated with [3H]-DHF was 43% greater in the presence of FdUrd and MTX than in the presence of MTX alone. As the rate of [3H]-dUrd incorporation into DNA was reduced by 88% and 99% by pretreating cells with 0.1 muM and 1 muM FdUrd, respectively, the inhibitory effect of MTX on [14C]-formate incorporation into (a) RNA was decreased by 63% and 46%; (b) DNA was decreased by 74% and 61%; and (c) protein was decreased by 63% and 32%. These data suggest that fluoropyrimidines can antagonize the effects of MTX on purines or nucleic acid synthesis and protein synthesis by preventing the consumption of THF for dTMP synthesis.
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005467:Floxuridine / Q000494:pharmacology*; D005561:Formates / Q000378:metabolism; D066298:In Vitro Techniques; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000378:metabolism
D004273:DNA, Neoplasm; D005561:Formates; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D013763:Tetrahydrofolates; D005467:Floxuridine; D008727:Methotrexate