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 decreased drug accumulation at the intracellular site of drug action. When due to increased energy-dependent drug efflux, this transport change is often associated with increased expression of an efflux pump for various lipophilic compounds, for example the P-glycoprotein which is the product of the MDR-1 gene. However, previously described HL-60 human promyelocytic leukemia cell lines resistant to the cytotoxic effect of anthracyclines have been reported not to express P-glycoprotein. We have isolated, by drug selection, an anthracycline-resistant HL-60 cell line that, in comparison to parental drug sensitive cells, exhibits a multidrug resistant phenotype including diminished intracellular drug retention, cross-resistance to multiple cytotoxic drugs, increased expression of a monoclonal antibody C219-reactive 180 kDa P-glycoprotein detected by Western blot analysis as well as increased expression of MDR-1 mRNA as determined by Northern blot and solution hybridization/RNAse protection analyses. Evidence is presented that the anthracycline-resistant HL-60 cells have amplified the MDR-1 gene.