INHIBITION OF P-GLYCOPROTEIN AND RECOVERY OF DRUG-SENSITIVITY OF HUMAN ACUTE LEUKEMIC BLAST CELLS BY MULTIDRUG-RESISTANCE GENE (MDR1) ANTISENSE OLIGONUCLEOTIDES

To overcome the problem of multidrug resistance, we investigated the e ffectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) i n suppressing multidrug resistance gene (mdr1) expression in drug-resi stant acute myelogenous leukemia (AML) blast cells and the K562 adriam ycin-resistant cell line K562/ADM. The percentage of cells with the md r1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% b y 20 mu mol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% b y 2.5 mu mol/L MDR1-AS in the AML blast cells. Western blot analysis a lso showed a decrease in the amount of P-gp in the MDR1-AS-treated K56 2/ADM cells. This effect was specific to MDR1-AS, and not observed wit h sense or random control oligonucleotides. The expression of mdr1 mRN A in K562/ADM and AML blast cells treated with MDR1-AS was decreased c ompared with the random control. Intracellular rhodamine retention and [H-3]daunorubicin also increased after antisense treatment. Chemosens itivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucle otides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia. (C) 1998 by The American Society of Hematology .