DEVELOPMENT OF EXTENDED MULTIDRUG-RESISTANCE IN HL-60 PROMYELOCYTIC LEUKEMIA-CELLS

In an attempt to mimic clinical conditions for the treatment of leukae mia, the HL60 promyelocytic cell line was treated for 18 h with low, c linically relevant, levels of the anthracycline epirubicin and the Vin ca alkaloid vinblastine. The resulting drug-resistant sublines not onl y expressed P-glycoprotein and the MDR phenotype but were also cross-r esistant to chlorambucil, methotrexate and cisplatinum, and had increa sed resistance to radiation. Development of resistance was associated with an aberrant differentiation phenotype with decreased expression o f myeloid antigens and expression of glycophorin A, an antigen normall y associated with erythroid differentiation. The ability of HL60 cells to terminally differentiate in response to all-trans-retinoic acid (v itamin A acid) was lost in the sublines. These results suggest that ei ther a single novel mechanism is responsible for multiple drug resista nce or the initial response to drug treatment is the co-induction of m ultiple mechanisms. These cells and the method by which they were gene rated therefore provide a clinically relevant model for the study of t he initial events in the development of not only multidrug resistance but also the extended multiple drug resistance usually encountered in the treatment of leukaemia.