TOPOISOMERASE INHIBITORS POTENTIATE TBE EFFECT OF RETINOIC ACID ON CELL-GROWTH INHIBITION AND INDUCTION OF DIFFERENTIATION OF LEUKEMIA HL-60 CELLS

Camptothecin (CPT) and 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP16) at concentrations of 0-10 nM and 0-400 nM, respectively, have weak synergistic effects with retinoic acid (RA) on the induction of differentiation and growth inhibition of HL-60 cells. However, pretreatment of HL-60 cells with the above respective concentrations of CPT or VP16 for 1 h, had no influence on the differentiation of HL-60 cells induced by the following treatment with RA: when HL-60 cells were pretreated with CPT or VP16 at concentrations of 80 nM or 16 mu M, respectively, the following treatment with RA had a synergistic effect on the induction of differentiation and growth inhibition. Morphology and biochemical markers were used to show that the differentiation-inducing effect of RA on HL-60 cells was potentiated by pretreatment with higher concentrations of 80 nM CPT or 16 mu M VP16. The present results suggest that combination of CPT or VP16 at low concentration with RA or pretreatment with higher concentrations of camptothecin or VP16, followed by RA treatment may be useful for increasing the differentiation effect of RA and decreasing the side effects of RA.