In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia.
Recent results show that the intracellular uptake pattern of idarubicin (IDA) in multidrug-resistant (MDR) cells is nearly identical to that seen in the drug-sensitive parent cell line, whereas the MDR cells have minimal daunorubicin (DNR) uptake compared with the drug-sensitive parent cells. It is known that the major metabolite of IDA, idarubicinol (IDA-OL), has nearly the same cytotoxicity as IDA, while the cytotoxicity of daunorubicinol (DNR-OL) is about 1/30th of that of DNR. We examined the effect of the MDR modifiers verapamil and dexniguldipine on the efflux of IDA, DNR and their hydroxylated metabolites IDA-OL and DNR-OL in blast populations of acute myeloid leukemia (AML), in the MDR-negative cell line CEM-CCRF and in their MDR-positive counterpart (CEM-VBL). All patients with relapsed or persistent AML had been pretreated with IDA and cytosine arabinoside. The efflux of the anthracyclines was estimated by flow cytometry. A total of 36 patients with AML were investigated; 18 out of 36 AML blast populations showed an efflux of DNR, DNR-OL and IDA-OL. The efflux of DNR, DNR-OL and particularly IDA-OL could be reversed by 10 microM verapamil or 1 microM dexniguldipine. For IDA we found an effusion of 40 +/- 11% in all blast populations which could not be significantly inhibited by the modulators. Similar results for IDA were found in the MDR-positive cell line (CEM-VBL 100) and in their MDR-negative counterpart (CEM-CCRF). The incubation of CEM-CCRF cells with DNR, DNR-OL, IDA-OL and especially IDA led to MDR induction as determined by reverse transcription/polymerase chain reaction analysis with MDR-specific primer and by cellular efflux studies. We conclude that the outcome of chemotherapy with idarubicin is influenced by MDR, although IDA is not essentially MDR-dependent itself, but because IDA-OL is actively involved in multidrug resistance. Further investigations should consider the question of whether the combination of IDA and MDR modifiers can enhance the serum level of the active metabolite IDA-OL and can reverse the MDR pattern in cells treated with IDA.
Schröder
J K
JK
Department of Internal Medicine (Cancer Research), University of Essen Medical School, Universitätsklinikum Essen, Hufelandstr. 55, D-45122 Essen, Germany. jan.schroeder@uni-essen.de
Kasimir-Bauer
S
S
Seeber
S
S
Scheulen
M E
ME
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001752:Blast Crisis; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015255:Idarubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C054440:idarubicinol; D014700:Verapamil; C000847:daunorubicinol; C054074:niguldipine; D015255:Idarubicin; D003630:Daunorubicin