Mechanism for resistance to 5-fluorouracil in P388 leukemia cells

In order to assess mechanisms for acquired resistance to 5-fluorouracil (5-FU) of P388 cells on a cellular basis, we compared sensitivities of P388 and its 5-FU-resistant subline (P388/5-FU) cells to 5-FU, 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd). P388/5-FU cells exhibited an approximately 10-fold resistance to 5-FU and 170-fold cross-resistance to FUrd but not to FdUrd when they were exposed to each agent for 5 h in vitro. 5-FU-induced growth inhibition was hardly reversed with thymidine, suggesting its ribonucleic acid (RNA)-directed effect. This was supported by the fact that similar amounts of 5-FU were incorporated into cellular RNA in P388 and P388/5-FU when these cells were incubated with equitoxic concentrations of 5-FU. Furthermore, incorporation of 5-FU and FUrd into cellular RNA in P388/5-FU cells were significantly lower than in P388 cells when cells were exposed to them at the same concentration. These results suggest a major action of 5-FU is directed toward RNA in these cells at least under the present experimental condition, and 5-FU resistance of this cell line is closely associated with reduced uridine kinase activity among various enzymatic changes previously observed.