RECOMBINANT HUMAN INTERLEUKIN-3 OPPOSES THE EFFECTS OF VITAMIN-A AND VITAMIN-D ON HL-60 HUMAN MYELOID-LEUKEMIA CELLS

Interleukin-3 (IL-3), retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (calcitriol) (vitamin D) have achieved' objective responses in phase I/II clinical trials in myeloid leukaemia and preleukaemia patients. In an effort to explore any additive or synergistic interactions between these biological agents which could provide the basis for improved therapeutic regimens for myeloid leukaemia patients, we have investigated the effects of Il-3 on both RA- and vitamin D-induced actions in HL-60 human myeloid leukaemia cells, which have receptors for these three agents, in both clonogenic microassays and liquid suspension cultures. The proliferative stimulus of IL-3 overrode and reversed the antiproliferative actions of both RA and vitamin D, the latter being more sensitive to the counteracting effect of IL-3. Whereas only high concentrations of IL-3: 1000 or more U/ml were able to oppose the antiproliferative effect of RA, all concentrations of IL-3 including the low concentration of 10 U/ml, significantly counteracted the antiproliferative action of vitamin D. RA restrained the proliferative stimulus of IL-3 partly at low physiological concentrations and almost completely at high pharmacological concentrations. The same results were reproduced in liquid suspension culture. Whereas RA restrained the proliferative stimulus of IL-3, vitamin D failed to restrain it. However, IL-3 did not induce differentiation or affect PA- or vitamin D-induced differentiation of HL-60 cells. The present results suggest that the clinical use of the combination of low concentration of IL-3 with RA and not with vitamin D might restrain the progression of myeloid leukaemia incurred during the treatment with IL-3 in some preleukaemic patients.