Low frequency of activity of P-glycoprotein (P-170) in acute lymphoblastic leukemia compared to acute myeloid leukemia.
The purpose of our investigations was to measure P-glycoprotein (P-170) activity in blast cells of 35 adults with acute myeloid leukemia (AML), and 24 children and adults with acute lymphoblastic leukemia (ALL) at time of diagnosis. Studies were based on a flow cytometric assay that detects efflux of the fluorescent dye rhodamine 123 (Rh123), which is transported from the cell by the P-170 pump. Dual-fluorescence staining with Rh123 and phycoerythrin-labeled monoclonal antibodies allowed selective measurement of Rh123 efflux in blast cells. Samples were scored positive when the fraction of blast cells showing Rh123 efflux exceeded 10% after a 120-min incubation. Activity of P-170 was observed in 19 (54%) of the 35 AML cases and was completely blocked in the presence of multidrug resistance inhibitors. Efflux activity was significantly higher in CD34-positive AML samples (p < 0.02). All AML patients with the FAB-subtype M5 (n = 5) lacked Rh123 pumping activity (p < 0.03). The complete remission rate in response to induction chemotherapy was significantly higher for Rh123-negative (11/13, 85%) than for Rh 123-positive AML patients (4/15, 27%) (p < 0.007). At a median follow-up of 9 months overall survival was significantly shorter for Rh123-positive than for Rh123-negative patients (p < 0.05). In contrast to AML, we could detect Rh123 efflux in only two (8%) out of 24 ALL cases. The immunological subtypes of these two positive cases was of B-ALL and pre-T-ALL. Bone marrow cryostat sections from 13 AML and five ALL patients were further analyzed for staining with monoclonal antibodies MM4.17 and JSB1. Ten of 13 AML and two of five ALL cases expressed the MDR protein. Our results indicate that there is a rather low frequency of P-170 pumping activity in ALL compared with AML. Further, functional activity of P-170 contributes to chemoresistance in de novo AML.
Ludescher
C
C
Department of Internal Medicine, University of Innsbruck, Austria.
Eisterer
W
W
Hilbe
W
W
Gotwald
M
M
Hofmann
J
J
Zabernigg
A
A
Cianfriglia
M
M
Thaler
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D012074:Remission Induction; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D016019:Survival Analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D012235:Rhodamines; D003561:Cytarabine; D020112:Rhodamine 123; D008942:Mitoxantrone; D015255:Idarubicin; D003630:Daunorubicin