Selection and characterization of mycophenolic acid-resistant leukemia cells

We isolated four mycophenolic acid (MA) -resistant clones (MA0.4, MA2, MA5, MA20) of murine leukemia (L1210) cells which were 2- to 125-fold more resistant than the parent cells to MA and had a 4- to 50-fold increase in the activity of the enzyme inosine monophosphate dehydrogenase (IMPDase). The MA-resistant phenotype was unstable after passage of MA0.4, MA2, and MA5 without MA, but stable after passage of MA20 without MA. All MA-resistant cell lines lost IMPDase activity after passage without MA. However, only MA20 lost IMPDase activity after passage with MA. The enzyme from all cell lines had similar kinetic parameters. The levels of a single polypeptide of approximately 57,000 daltons was increased in MA5, and the levels decreased after passage of the cells without MA. These results indicate that three of the selected cell lines are resistant to MA because of an increase in the amount of enzyme IMPDase, while the stability of the resistant phenotype of MA20 and its less than expected IMPDase activity that this cell line may have a second mode of resistance.