Differentiation induction in non-lymphocytic leukemia cells upon treatmentwith mycophenolate mofetil

Inosine 5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting re action of guanine nucleotide biosynthesis and has been implicated in the re action of cell growth and differentiation. We investigated the ability of m ycophenolate mofetil, a prodrug of mycophenolic acid, to induce differentia tion in HL-60 and U937 leukemic cells as well as in fresh leukemia cells fr om patients with non-lymphocytic leukemia. Treatment with mycophenolate mof etil reduced the intracellular guanosine 5'-triphosphate (GTP) levels and i nduced morphologic and functional differentiation in HL-60 and U937 cells d ose-dependently. HL-60 and U937 cells developed macrophage-like cytoplasm a s well as the expression of CD 11b and CD14 antigens and the ability to oxi dize nitroblue tetrazorium (NBT). These changes became evident when the int racellular CTP levels decreased to approximately 20-30% of the untreated co ntrol level and were abrogated by the addition of guanosine. In the fresh l eukemic cells, differentiation induction was shown in the cells derived fro m seven of 13 patients. The fresh leukemia cells responding to mycophenolat e mofetil revealed significant higher positivity to CD11b CD14, and NET bef ore treatment and significantly reduced intracellular GTP levels after trea tment compared to the non-responding cells. These findings suggest that myc ophenolate mofetil induces differentiation in HL-60 and U937 cells and some fresh leukemia cells with moderate tendency to maturation, by causing a de crease in the intracellular GTP levels. Mycophenolate mofetil could be a pr omising differentiation inducer in vivo. (C) 2000 Elsevier Science Ltd. All rights reserved.