DIFFERENTIAL-EFFECTS OF UBENIMEX ON GROWTH OF NORMAL HUMAN HEMATOPOIETIC PROGENITORS AND LEUKEMIC-CELLS INVITRO

The effects of ubenimex on the growth of normal human haematopoietic cells and myeloid leukaemia cell-lines and the mechanisms of its action were studied in vitro. As for normal haematopoiesis, ubenimex stimulated the production of granulocyte (G) colony-forming activity from peripheral blood (PB) mononuclear cells (MNC), especially T cells. The activity was completely neutralized by antibodies against recombinant human (rh) granulocyte-macrophage (GM) colony-stimulating factor (CSF), suggesting that it is mainly GM-CSF. Further, ubenimex enhanced the G-, M- and megakaryocyte-colony formation stimulated by rhG-CSF, rhGM-CSF or rh interleukin 3 (IL-3), and the erythroid burst formation stimulated by rhIL-3 plus rh erythropoietin, when the added concentrations of G-CSF, GM-CSF and IL-3 were submaximal. This suggested that ubenimex increases the binding of these growth factors to normal haematopoietic progenitor cells, and/or that it inhibits the degradation of these factors. As for leukaemia cell-lines (HL60, KG-1 and K562), ubenimex directly inhibited the clonogenic cell growth dose-dependently when added to the agar cultures, and the growth of total cells and colony-forming cells when added to the liquid cultures for over 1 week. Further, ubenimex stimulated PB monocytes to generate some inhibitory factors against leukaemic colony-forming cells. The optimal concentration range of ubenimex for enhancement of normal haematopoiesis was 0.01-1-mu-g/ml, almost equivalent to serum concentrations obtained with clinical therpay, while that for inhibition of leukaemia cell growth was higher, although even at 0.1-10-mu-g/ml ubenimex could inhibit leukaemia cell growth when the cells were exposed for long periods of time.