INTERACTION OF VITAMIN-D DERIVATIVES AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN LEUKEMIC-CELL DIFFERENTIATION

The ability of the physiologically active form of vitamin D-3 1,25-dih ydroxyvitamin D-3 (1,25(OH)(2)D-3) and two novel vitamin D analogues, EB1089 and KH1060 to induce the differentiation of the U937 and HL-60 leukaemic cell lines was evaluated, alone or in combination with granu locyte-macrophage colony-stimulating factor (GM-CSF). Studies revealed that following 96 h treatment, the vitamin D derivatives inhibited th e proliferation, and induced the differentiation of U937 and HL 60 cel ls in a dose-dependent manner, as determined by cell counts and nitrob lue tetrazolium (NBT) reduction assays, respectively. EB1089 and KH106 0 were found to be more effective than 1,25(OH)(2)D-3 in exhibiting th eir antiproliferative and differentiative effects, In contrast, induct ion of leukaemic cell differentiation with 1 ng/ml GM-CSF after 96 h w as less effective when compared with the vitamin D derivatives used in dividually. Fluorescence activated cell scanning (FAGS) analyses indic ated that the vitamin D derivatives readily induced the expression of the monocyte-associated cell surface antigen, CD14, and also the beta( 2)-integrins, CD11b and CD18 in both cell lines after 48 h and 96 h tr eatment. The ability of EB1089 and KH1060 to induce these antigens was achieved with greater efficacy relative to the native hormone, When U 937 and HL-60 cell cultures were cotreated for 48 h with the vitamin D compounds and GM-CSF and analysed by FAGS, enhanced effects on CD14 a nd CD11b induction were observed compared to those of the compounds al one. These co-operative effects may occur as a consequence of molecula r events which involve the transcription by vitamin D receptors (VDR) of genes required for the responsiveness of immature cells to factors such as GM-CSF, and place these and other related vitamin D analogues as potential therapeutic agents in the treatment of leukaemia.