INHIBITION OF IMP DEHYDROGENASE BY MYCOPHENOLIC-ACID IN MOLT F4 HUMAN-MALIGNANT LYMPHOBLASTS

The effects of inhibition of inosine monophosphate dehydrogenase (IMPD H), the rate-limiting enzyme in guanine nucleotide de novo synthesis, on cell growth, cell viability, endogenous nucleotide concentrations a nd concentrations of extracellular nucleosides and bases were studied in Molt F4 human malignant lymphoblasts. Mycophenolic acid (MPA) was u sed as a specific inhibitor of the enzyme activity. IMPDH activity was maximally inhibited with 0.5 mu M MPA. After a 2 h exposure of the ce lls to 0.5 mu M MPA, guanine nucleotides were depleted to approximatel y 50% of control values, whereas 5-phosphoribosyl-1-pyrophosphate leve ls increased to approximately 200%. Under these conditions, cytotoxici ty became obvious after 24 h. Depletion of guanine nucleotides and cyt otoxicity were prevented by addition of guanosine to MPA treatment. Da ily supplements of guanosine were required to prevent MPA cytotoxicity during the entire incubation period of 72 h. We conclude that depleti on of guanine nucleotides, induced by treatment with MPA, induces a se vere and rapid cytotoxicity in Molt F4 cells.