Development of extended multidrug resistance in HL60 promyelocytic leukaemia cells.
In an attempt to mimic clinical conditions for the treatment of leukaemia, the HL60 promyelocytic cell line was treated for 18 h with low, clinically relevant, levels of the anthracycline epirubicin and the Vinca alkaloid vinblastine. The resulting drug-resistant sublines not only expressed P-glycoprotein and the MDR phenotype but were also cross-resistant to chlorambucil, methotrexate and cisplatinum, and had increased resistance to radiation. Development of resistance was associated with an aberrant differentiation phenotype with decreased expression of myeloid antigens and expression of glycophorin A, an antigen normally associated with erythroid differentiation. The ability of HL60 cells to terminally differentiate in response to all-trans-retinoic acid (vitamin A acid) was lost in the sublines. These results suggest that either a single novel mechanism is responsible for multiple drug resistance or the initial response to drug treatment is the co-induction of multiple mechanisms. These cells and the method by which they were generated therefore provide a clinically relevant model for the study of the initial events in the development of not only multidrug resistance but also the extended multiple drug resistance usually encountered in the treatment of leukaemia.
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G M
GM
Neurobiology Unit, University of Technology, Sydney, Gore Hill, N.S.W., Australia.
Davey
M W
MW
Davey
R A
RA
Kidman
A D
AD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D018432:Drug Resistance, Multiple; D015251:Epirubicin / Q000627:therapeutic use*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014212:Tretinoin / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000627:therapeutic use; D014747:Vinblastine / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D008717:Methionine Sulfoximine; D015251:Epirubicin; D019328:Buthionine Sulfoximine; D014212:Tretinoin; D014747:Vinblastine; D014700:Verapamil