Flow cytometric determination of the multidrug-resistant phenotype in acute leukemia.
Expression of the multidrug-resistant (MDR) phenotype was investigated in acute leukemia using a monoclonal antibody (HYB-241) directed against a cell surface epitope of the 180 kd P-glycoprotein (gp180) by flow cytometric analysis of clinical samples. Samples from sixty-four patients were tested (37 with acute myelocytic leukemia, 20 with acute lymphocytic leukemia, and 7 with blastic chronic myelocytic leukemia). A D value (derived from Kolmogorov-Smirnov test) greater than 0.15 was considered positive (+). Eight of 32 newly diagnosed patients were positive for gp180 compared with 22 of 32 relapsed/refractory (R/R) patients (P < 0.001). Of the new patients, vinca/anthracycline-based induction therapy failed in 3/6 gp180(+) and 5/18 gp180(-) patients. In the R/R group, 15/16 gp180(+) and 3/6 gp180(-) patients failed to achieve complete remission (P < 0.05). In vitro drug accumulation studies performed with verapamil failed to show a correlation with clinical response. However, in a subset of patients, a striking correlation (r = .97, P = .001) was noted between the presence of gp180 as determined by the D value and the functional activity of the P-glycoprotein as expressed by increased daunorubicin accumulation in the presence of verapamil. The results suggest that 1) newly diagnosed patients can express gp180, 2) P-glycoprotein is expressed in 69% of R/R patients, 3) response in R/R patients is effected by the presence of gp180, and 4) expression of gp180 is highly correlated with its function as a drug-efflux pump in a subset of the patients studied. The complexity of clinical drug resistance is underscored by the finding that the MDR model is not applicable to all cases. In such instances, other mechanisms may play a predominant role.
Maslak
P
P
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Hegewisch-Becker
S
S
Godfrey
L
L
Andreeff
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001692:Biological Transport; D001752:Blast Crisis / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D007951:Leukemia, Myeloid / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D012074:Remission Induction; D016879:Salvage Therapy; D017211:Treatment Failure; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D014750:Vincristine; D014747:Vinblastine; D014700:Verapamil; D003630:Daunorubicin