Expression of a 95 kDa membrane protein is associated with low daunorubicin accumulation in leukaemic blast cells.
A 95 kDa membrane protein (P-95) has been previously noted to be overexpressed in a doxorubicin-resistant subline of the MCF-7 breast cancer line and in clinical samples obtained from patients with solid tumours refractory to doxorubicin. We performed Western blotting on blast cell lysates from adults with acute myeloid leukaemia, using antisera to P-95. Concomitant flow cytometric assays measured daunorubicin accumulation and retention. Blasts from 16/46 patient samples had detectable P-95 and had reduced accumulation of daunorubicin compared with the negative marrows. Experiments with the P-95 positive MCF-7 multidrug-resistant subline demonstrated decreased daunorubicin accumulation and retention relative to the sensitive parent line. AML blast cells positive for P-95 also demonstrated greater overall in vitro survival in the presence of daunorubicin relative to the P-95-negative samples. The expression of P-95 did not correlate with failure to achieve an initial complete remission with daunorubicin and cytarabine induction chemotherapy. We conclude that the P-95 protein may possess an efflux transporter function, and may represent another mechanism responsible for anthracycline resistance in acute myeloid leukaemia.
Doyle
L A
LA
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201.
Ross
D D
DD
Sridhara
R
R
Fojo
A T
AT
Kaufmann
S H
SH
Lee
E J
EJ
Schiffer
C A
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis*; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000032:analysis*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D003630:Daunorubicin