DIFFERENTIATION INDUCTION OF HL60 CELLS BY 1,25(OH)(2)D-3, ALL-TRANS-RETINOIC ACID, RTGF-BETA(2) AND THEIR COMBINATIONS

1,25 Dihydroxyvitamin D-3 (D-3), all trans retinoic acid (atRA) and th e cytokine rTGF-beta(2) are growth and differentiation modulators of p romyelocytic leukemia. D-3 gives rise to a functional monocytic cell p opulation whereas single atRA therapy induces granulocytic cell featur es. rTGF-beta(2) reduces HL60 cell proliferation but has no differenti ating capacity. Combination treatment demonstrates additive effects be tween either D-3 and atRA or D-3 and rTGF-beta(2), resulting in a cell population with mixed characteristics since individual cells exhibit both monocytic as granulocytic cell features. The capacity of single a nd combined treatments to induce a permanent differentiation was inves tigated. Therefore, cells were preincubated with the drugs during six days, test drugs were removed and cell number was monitored. The total cell count of populations treated with single agents remains constant for only a few days and then increases rapidly. rTGF-beta(2) cooperat ed with Dg in inducing a long-lasting differentiation state (3 weeks). Addition of atRA to this combination did not significantly alter prol iferation or differentiation, but some cells underwent apoptosis. Ther efore, a total and permanent differentiation of leukemic cells may be achieved by repeated exposure to a combination of differentiation indu cing agents. Copyright (C) 1997 Elsevier Science Ltd.