MECHANISMS OF RETINOID RESISTANCE IN LEUKEMIC-CELLS - POSSIBLE ROLE OF CYTOCHROME-P450 AND P-GLYCOPROTEIN

Retinoic acid (RA) regulates the differentiation and proliferation of a wide variety of different cell types and all-trans RA induces comple te remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, clinical resistance to retinoids may develop and poses a serious problem for differentiation-inducing therapy. We studied the effects of RA in combination with a cytochrome P450 inhibi tor (clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth and differentiation of RA-resistant HL-60 cells and fresh HA-r esistant leukemic cells from two APL patients. RA-resistant HL-60 cell s and APL cells differentiated to mature granulocytes when cultured wi th all-trans RA and either clotrimazole and verapamil but not with eit her of the agents alone. These findings were confirmed in these cells by their increased expression of CD11b antigen and migration-inhibitor y factor-related protein-8/14 mRNAs and decreased levels of c-myc mRNA . These combinations also markedly decreased the number of viable cell s and inhibited cellular proliferation. After isolation of microsomes, measurements showed that levels of cytochrome P450 activities in both wild-type and RA-resistant HL-60 cells were almost comparable. Moreov er, expression of the CYP1A1-type cytochrome P450 gene could not be de tected in either cell type. However, RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells and APL cells, expressed multi drug-resistance-1 gene transcripts. Taken together, acquired resistanc e to RA may be explained in part by drug metabolism in leukemic cells. Possible mechanisms for accelerated clearance of RA include the induc tion of non-CYP1A1 cytochrome P450 enzymes and P-glycoprotein. (C) 199 6 by The American Society of Hematology.