P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia.
Despite treatment with intensive chemotherapy, a considerable number of patients with acute myeloid leukemia (AML) die from their disease due to the occurrence of resistance. Overexpression of the transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1 has been identified as a major cause of cross-resistance to functionally and structurally unrelated drugs. In the present study, the functional activity of P-gp and MRP was determined in 104 de novo AML patients with a flow cytometric assay using rhodamine 123 (Rh123) in combination with PSC833 and carboxyfluorescein (CF) in combination with MK-571. The results were compared with clinical outcome and with known prognostic factors. The functional activity of P-gp and MRP, expressed as Rh123 efflux blocking by PSC833 and CF efflux blocking by MK-571, demonstrated a great variability in the AML patients. A strong negative correlation was observed between Rh123 efflux blocking by PSC833 and Rh123 accumulation (r(s) = -0.69, P < 0.001) and between CF efflux blocking by MK-571 and CF accumulation (r(s) = -0.59, P < 0.001). A low Rh123 accumulation and a high Rh123 efflux blocking by PSC833 were associated with a low complete remission (CR) rate after the first cycle of chemotherapy (P = 0.008 and P = 0.01, respectively). Patients with both low Rh123 and CF accumulation (n = 16) had the lowest CR rate (6%), whereas patients with both high Rh123 and CF accumulation (n = 11) had a CR rate of 73%. AML patients with French-American-British classification M1 or M2 showed a lower Rh123 accumulation than patients with French-American-British classification M4 or M5 (P = 0.02). No association was observed between the multidrug resistance parameters and overall survival of the AML patients. Risk group was the only predictive parameter for overall survival (P = 0.003).
van der Kolk
D M
DM
Department of Hematology, University Hospital Groningen, the Netherlands.
de Vries
E G
EG
van Putten
W J
WJ
Verdonck
L F
LF
Ossenkoppele
G J
GJ
Verhoef
G E
GE
Vellenga
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D005452:Fluoresceins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003524:Cyclosporins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011422:Propionates; D011804:Quinolines; D012333:RNA, Messenger; D020112:Rhodamine 123; C024098:6-carboxyfluorescein; C059141:verlukast; C070272:valspodar