Antagonistic interactions of hexamethylene bisacetamide in combination with 1-beta-D-arabinofuranosylcytosine, adriamycin and harringtonine on the growth and differentiation of HL-60 cells in vitro.

Selective killing of cancer cells by cytotoxic agents and the conversion of cancerous cells to normal state by differentiation agents represent two basically different approaches in chemotherapy. In this study, we examined the combination of the cell differentiation inducer, hexamethylene bisacetamide (HMBA), and the cytotoxic agents, 1-beta-D-arabinofuranosylcytosine (Ara-C), adriamycin (Adr) and harringtonine (HT), for cytotoxicity and induction of cell differentiation in HL-60 cells by measuring cell growth inhibition, morphological maturation and nitroblue tetrazolium (NBT) reduction. To determine quantitatively whether the effects produced by these combinations were additive, synergistic or antagonistic, we used a computer program based on the median-effect principle and isobologram equations (Adv. Enz. Reg. 22, 27-55, 1984), After 5-day exposure to each drug alone we found that the ED50s for cell growth inhibition were 0.01 microM for Ara-C, 0.012 microM for Adr, 0.017 microM for HT and 2.53 mM for HMBA. ED50s for differentiation were 0.089 microM (morphology), 0.06 microM (NBT) for Ara-C; 0.12 microM (morphology), 0.09 microM (NBT) for Adr; 0.04 microM (morphology) 0.06 microM (NBT) for HT; and 2.55 mM (morphology), 2.43 mM (NBT) for HMBA, respectively. At dose levels from ED50 to ED95, the combinations of Adr/HMBA and HT/HMBA produced antagonistic cytotoxic and cell differentiation effects. The combination of Ara-C/HMBA produced antagonistic cytotoxic and cell differentiation effects. The combination of Ara-C/HMBA produced antagonistic cytotoxic effects but slight synergistic cell differentiation effects. On the basis of this study, we conclude that the equipotency combinations of the above three pairs of drugs do not synergistically enhance cytotoxicity or cell differentiation effects in vitro at effect levels high enough for the successful treatment of acute leukemia. Other combinations of cell differentiation agents with cytotoxic agents or biological response modifiers remain to be explored.