Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration.
A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.
Kavallaris
M
M
Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, Randwick, Sydney, N.S.W., Australia.
Haber
M
M
Norris
M D
MD
Pittman
S M
SM
Reed
C
C
Stewart
B W
BW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000032:analysis; D008727:Methotrexate / Q000494:pharmacology*; D010641:Phenotype; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D003609:Dactinomycin; D014750:Vincristine; D014747:Vinblastine; D014700:Verapamil; D008727:Methotrexate