Effect of 5Fluorouracil on RNA Metabolism in Novikoff Hepatoma Cell&

The resistance of a Novikoff hepatoma cell line (Ni -Si I FdUrd) to 5-fluorouracil (FUra) was reversed by the inclusion of inosine in the culture medium. As the concentration of inosine in the medium was increased, there was a marked increasein the uptakeof [14C]FUra nd conversionto nucleo tides with a corresponding increase in the incorporation into RNA. While FUra alone had no effect on this resistant cell line, the combination of FUra plus inosine altered the levels of ribose 1-phosphate but not 5-phosphoribosyl 1-pyrophosphate, al tered the maturation of precursor ribosomal RNA by blocking the formation of 185 RNA, altered the methylation of the ribosomal RNA, and caused inhibition of the growth of these cells. No evidence was obtained that fluorodeoxyuridine 5'monophosphate was formed in the Ni -Si /FdUrd cells as a result of treatment with FUra plus inosine. In addition, the metabolism of [3H]deoxycytidine in the presence of FUra plus inosine in the intact Ni -Si /FdUrd cells did not indicate signif icant inhibition of thymidylate synthetase as evidenced by the levels of deoxyuridine 5'-rnonophosphate or conversion to thymidine 5'-monophosphate.