USE OF ARSENIC TRIOXIDE (AS2O3) IN THE TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA (APL) .1. AS2O3 EXERTS DOSE-DEPENDENT DUAL EFFECTS ON APL CELLS

Recent clinical studies in China showed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As2O3 can trigger apoptosis of APL ce ll line NB4 cells, which is associated with downregulation of bcl-2 ge ne expression and modulation of PML-RAR alpha chimeric protein. To fur ther understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrat ions of As2O3 on cultured primary APL cells, all-trans retinoic acid ( ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL ce ll lines. The results indicated that As2O3 had dose-dependent dual eff ects on APL cells: inducing preferentially apoptosis at relatively hig h concentrations (0.5 to 2 mu mol/L) and inducing partial differentiat ion at low concentrations (0.1 to 0.5 mu mol/L). The rapid modulation and degradation of PML-RAR alpha proteins, which was induced by As2O3 at 0.1 to 2 mu mol/L, could contribute to these two effects. Bone marr ow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerat ive cells increased after 2 to 3 weeks of continuous in vivo As2O3 tre atment when leukemic promyelocytes decreased. In conclusion, combinati on of induction of apoptosis and partial differention could be the mai n cellular mechanisms of As2O3 in the treatment of APL, and PML-RAR al pha could play an important role in determining the specific effects o f As2O3 on APL cells. (C) 1997 by The American Society of Hematology.