In vitro effect of GF120918, a novel reversal agent of multidrug resistance, on acute leukemia and multiple myeloma cells.
Resistance to chemotherapy in multiple myeloma (MM) and acute myeloid leukemia (AML) is frequently caused by multiple drug resistance (MDR), characterized by a decreased intracellular drug accumulation. MDR is associated with expression of P-glycoprotein (P-gp). GF120918, an acridine derivative, enhances doxorubicin cell kill in resistant cell lines. In this study, the effect of GF120918 on MDR cell lines and fresh human leukemia and myeloma cells was investigated. The reduced net intracellular rhodamine-123 (Rh-123) accumulation in the MDR cell lines RPMI 8226/Dox1, /Dox4, /Dox6 and /Dox40 as compared with wild-type 8226/S was reversed by GF120918 (0.5-1.0 microM), and complete inhibition of rhodamine efflux was achieved at 1-2 microM. This effect could be maintained in drug-free medium for at least 5 h. GF120918 reversal activity was significantly reduced with a maximum of 70% in cells incubated with up to 100% serum. GF120918 significantly augmented Rh-123 accumulation in vitro in CD34-positive acute leukemia (AML) blasts and CD38-positive myeloma (MM) plasma cells obtained from 11/27 de novo AML and 2/12 refractory MM patients. A significant correlation was observed between a high P-gp expression and GF120918 induced Rh-123 reversal (P=0.0001). Using a MRK16/IgG2a ratio > or = 1.1, samples could be identified with a high probability of GF120918 reversal of Rh-123 accumulation. In conclusion, GF120918 is a promising MDR reversal agent which is active at clinically achievable serum concentrations.
den Ouden
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Department of Hematology, University Hospital Dijkzigt and Erasmus University, Rotterdam, The Netherlands.
van den Heuvel
M
M
Schoester
M
M
van Rens
G
G
Sonneveld
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000166:Acridines / Q000378:metabolism / Q000494:pharmacology*; D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000964:Antimetabolites, Antineoplastic; D007546:Isoquinolines; D009363:Neoplasm Proteins; D012235:Rhodamines; D044005:Tetrahydroisoquinolines; D020112:Rhodamine 123; C083501:Elacridar