Abstract
Although 5-fluorouracil (FUra) incorporates in all species of RNA, the molecular basis for producing cytotoxicity by RNA-related mechanisms remains unclear. We have studied the effects of FUra on the synthesis of alpha- and beta-globin mRNA in murine erythroleukemia cells. An analysis of equivalent amounts of RNA from FUra-treated cells suggested that this agent causes a relative increase in globin mRNA. However, when RNA obtained from the same number of cells was analyzed, thus taking into account decreases in ribosomal RNA, the amount of intracellular alpha- or beta-globin mRNA actually decreased following FUra treatment. The decrease in globin mRNA was associated with decreases in both intracellular globin and hemoglobin content. The findings thus indicate that FUra inhibits the accumulation of alpha- and beta-globin transcripts. This effect of FUra could occur by decreasing transcriptional rate or, as in the case of ribosomal RNA, by interfering with the processing of these nucleic acids. Either mechanism could contribute to the RNA-related cytotoxicity induced by this agent.
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