Extended multidrug resistance in haemopoietic cells

The development of drug resistance was studied in a series of haemopoietic cells to determine its relationship to cell lineage. Treatment of the U937 monocytic cell line with epirubicin (15 ng/ml) or vinblastine (8 ng/ml) induced drug-resistant sublines with cross-resistance to epirubicin (8- and 16-fold respectively), vinblastine (5- and 20-fold), paclitaxel (15- and 42-fold) and etoposide (19- and 13-fold). However, sublines were also 3-5-fold resistant to the alkylating agent chlorambucil, cis-platinum and methotrexate, demonstrating an extended multidrug resistance (MDR) phenotype. These cells oner-expressed P-glycoprotein, but decreased drug accumulation was not restored in the presence of verapamil, suggesting that the P-glycoprotein was not functional. Similar drug treatment of the HL60 promyelocytic cell line also produced sublines exhibiting an extended MDR phenotype. The KGla and the HEL cell lines expressed functional P-glycoprotein and were resistant to the drug concentrations used for treatment. Multidrug resistance as mediated by P-glycoprotein cannot explain the resistance of CML patients to chemotherapy, especially in blast crisis. The induction of an extended MDR phenotype specifically in myeloid cells in response to drug treatment may explain the resistance observed in the treatment of CML.