dexniguldipine and Leukemia--Myeloid--Acute

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.

Topics: Antineoplastic Agents; Blast Crisis; Calcium Channel Blockers; Daunorubicin; Dihydropyridines; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Idarubicin; Leukemia, Myeloid, Acute; Tumor Cells, Cultured; Verapamil

The newly designed pyridine derivative B9309-068 and a series of structurally different compounds were tested for their ability to modulate rhodamine 123 (RHO) efflux from CD56+ hematopoietic cells in the presence of either 10% fetal calf serum or undiluted human AB serum. Furthermore, efflux modulation was investigated on CD34+ blast populations obtained from four patients with relapsed state AML. Target cells were specified throughout by labeling with peridinine chlorophyll protein (PerCP)-conjugated monoclonal antibodies, allowing clear differentiation from RHO emission spectrum by flow cytometry. In the presence of low serum each compound efficiently modulated RHO efflux without significant differences in the range of final concentrations (1.0-3.0 microM). At 0.1 microM, however, RHO efflux was differentially modulated following the series GF120918 approximately B9309-068 > PSC 833 > DNIG approximately DVER. With CD56+ cells in the presence of undiluted human AB serum at a final modulator concentration of 0.1 microM, all chemosensitizers tested were found to be inefficient. At final concentrations of 0.3 microM or higher, distinct RHO efflux modulation was found with the following efficacies: B9309-068 approximately GF120918 > PSC 833 >> DVER approximately DNIG. The efficacies seen in undiluted human AB serum at 3.0 microM were comparable to those seen on CD56+ cells at final modulator concentrations of 0.1 microM in low serum. Our results identify the pyridine derivative B9309-068 as a promising compound for modulating P-glycoprotein-mediated drug resistance under conditions resembling the clinical setting. Nonetheless, modulation potencies of a series of structurally very different chemosensitizers was revealed to be substantially diminished at high serum concentrations in vitro.

Topics: Acridines; Antigens, CD34; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Blood Proteins; Calcium Channel Blockers; CD56 Antigen; Cyclosporins; Dihydropyridines; Dose-Response Relationship, Drug; Flow Cytometry; Fluorescent Dyes; Gene Expression; Humans; Isoquinolines; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Morpholines; Multidrug Resistance-Associated Proteins; Pyrimidines; Rhodamine 123; Rhodamines; Tetrahydroisoquinolines; Verapamil