EXTENDED MULTIDRUG-RESISTANCE IN HEMATOPOIETIC-CELLS

The development of drug resistance was studied in a series of haemopoi etic cells to determine its relationship to cell lineage. Treatment of the U937 monocytic cell line with epirubicin (15 ng/ml) or vinblastin e (8 ng/ml) induced drug-resistant sublines with cross-resistance to e pirubicin (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 chlora mbucil, cis-platinum and methotrexate, demonstrating an extended multi drug resistance (MDR) phenotype. These cells oner-expressed P-glycopro tein, 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 produc ed 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 me diated by P-glycoprotein cannot explain the resistance of CML patients to chemotherapy, especially in blast crisis. The induction of an exte nded MDR phenotype specifically in myeloid cells in response to drug t reatment may explain the resistance observed in the treatment of CML.