INDUCTION OF DIFFERENTIATION IN ACUTE PROMYELOCYTIC LEUKEMIA-CELLS BY9-CIS RETINOIC ACID ALPHA-TOCOPHEROL ESTER (9-CIS TRETINOIN TOCOFERIL)

Acute promyelocytic leukemia (APL) has a specific genetic rearrangemen t between the retinoic acid receptor (RAR)-alpha gene and the pml nucl ear protein gene: All-trans retinoic acid (ATRA) induces granulocytic differentiation of APL-derived cells and is used to treat APL patients . However, ATRA interacts with normal cells with RAR throughout the en tire body, and when used at high doses or over a long duration, it ind uces several adverse effects. The development of drugs that selectivel y act on APL cells may contribute to increasing the therapeutic effica cy of APL treatment as well as elucidating the mechanisms of response to ATRA. In this study, 9-cis retinoic acid alpha-tocopherol ester (9C TT) inhibited the proliferation of APL-derived NB4 and HT93 cells and induced differentiation markers, such as granulocytic maturation, nitr oblue tetrazolium reduction, and CD11b expression, in these cells. The effects of 9CTT on non-APL cells, including HL-60 and U937 cells, wer e much weaker than those on APL cells, and tretinoin tocoferil (TT), w hich is an alpha-tocopherol ester of ATRA, did not induce the differen tiation of APL cells as effectively as 9CTT. The differentiation-induc ing effects of 9CTT were inhibited by RAR antagonists. 9CTT and TT sim ilarly induced the transactivating activity of RARs, but were not effe ctive on RXRs. 9CTT downregulated the expression of PML/RAR-alpha prot ein more effectively than TT,which suggests that it may tie involved i n the selectivity of 9CTT against APL cells. Interestingly, 9CTT enhan ced the differentiation of APL cells induced by ATRA, 9-cis retinoic a cid, and synthetic retinobenzoic acids. Combined with 1 alpha,25-dihyd roxyvitamin D-3 (VD3), 9CTT also more than additively induced the diff erentiation of APL cells. Thus, 9CTT, alone dr in combination with oth er retinoids or VD3, may tie useful for the treatment of APL. (C) 1998 by The American Society of Hematology.