CHARACTERIZATION OF AN ANTHRACYCLINE-RESISTANT HUMAN PROMYELOCYTE LEUKEMIA (HL-60) CELL-LINE WITH AN ELEVATED MDR-1 GENE-EXPRESSION

Multidrug resistance to a variety of cytotoxic drugs is due to decreas ed drug accumulation at the intracellular site of drug action. When du e to increased energy-dependent drug efflux, this transport change is often associated with increased expression of an efflux pump for vario us lipophilic compounds, for example the P-glycoprotein which is the p roduct of the MDR-1 gene. However, previously described HL-60 human pr omyelocytic leukemia cell lines resistant to the cytotoxic effect of a nthracyclines have been reported not to express P-glycoprotein. We hav e isolated, by drug selection, an anthracycline-resistant HL-60 cell l ine that, in comparison to parental drug sensitive cells, exhibits a m ultidrug resistant phenotype including diminished intracellular drug r etention, cross-resistance to multiple cytotoxic drugs, increased expr ession of a monoclonal antibody C219-reactive 180 kDa P-glycoprotein d etected by Western blot analysis as well as increased expression of MD R-1 mRNA as determined by Northern blot and solution hybridization/RNA se protection analyses. Evidence is presented that the anthracycline-r esistant HL-60 cells have amplified the MDR-1 gene.