DIFFERENTIATION INDUCTION IN NONLYMPHOCYTIC LEUKEMIA-CELLS UPON TREATMENT WITH MIZORIBINE

Inosine-5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiti ng reaction of guanine nucleotide biosynthesis and has been implicated in the reaction of cell growth and differentiation. We examined the a bility of mizoribine, an IMP dehydrogenase inhibitor, to induce differ entiation in HL-60 and U937 cells as well as in fresh leukemic blast c ells from patients with non-lymphocytic leukemia. Treatment with mizor ibine reduced intracellular GTP levels and induced morphologic and fun ctional differentiation in these two cell lines in a dose-dependent ma nner. HL-60 and U937 cells developed polymorphic nuclei and macrophage -like cytoplasm, respectively, as well as expression of CD11b and CD14 antigens and the ability to oxidize NBT. These changes became evident when intracellular GTP levels decreased to approximately 30% of untre ated controls and were abrogated by addition of guanosine to the media . However, in fresh leukemic cells, the cells showing maturation in re sponse to mizoribine were limited in those derived from two of ten pat ients having non-lymphocytic leukemia. These findings suggest mizoribi ne could induce differentiation in HL-60 and U937 cells through a decr ease of intracellular GTP levels. Further study is required to determi ne its clinical use in patients with acute non-lymphocytic leukemia. ( C) 1997 Elsevier Science Ireland Ltd.