Cellular uptake and antiproliferative effects of therapeutic concentrations of idarubicin or daunorubicin and their alcohol metabolites, with or without cyclosporin A, in MDR1+ human leukemic cells.
Ways of restoring an altered drug sensitivity in P-170 glycoprotein (MDR1) positive leukemias are being actively sought for, mostly using MDRI negative regulators together with the MDR1-sensitive anthracycline-type drugs daunorubicin and mitoxantrone. Because idarubicin is less vulnerable to MDR1-mediated transport and could thereby represent a better companion to MDR1 inhibitors, we assessed the ability of the anti-MDR1 agent cyclosporin A to modulate this function in multidrug resistant T-lymphoblastic CEM cells challenged in vitro with either daunorubicin or idarubicin. In order to obtain information of potential interest for the design of a clinical trial, we adopted drug plus metabolite concentrations and exposure times close to the in vivo pharmacokinetics of equimyelotoxic doses of intravenous daunorubicin 45 mg/m2 or idarubicin 10-12 mg/m2, respectively, plus infusional cyclosporin A 16 mg/kg/d. Study methods were cytofluorimetry for the detection of intracellular drug uptake, retention and pro-apoptotic effects (binding of fluoresceinated annexin V), and the standard MTT assay as growth inhibition test. The results showed significantly greater drug uptake (at 30'), retention (at 12 hours), and apoptotic cell rates with idarubicin+/-idarubicinol than daunorubicin+/-daunorubicinol (p<0.05), and a further potentiation of these effects by cyclosporin A. Differing from daunorubicin, idarubicin intracellular accumulation and, by inference, related apoptotic changes were increased by cyclosporin A only in the early phase of drug-cell interaction; a potential advantage towards a reduced toxicity by CsA delivered as short rather than prolonged infusion in the in vivo setting. MTT assay results were also in favour of idarubicin but greatly influenced by cyclosporin A itself. Altogether, study results in MDR1+ cells incubated with CsA 1500 ng/ml plus idarubicin+idarubicinol 100+20 ng/ml, that are peak levels achievable in vivo with an idarubicin dose > or = 12 mg/m2 plus cyclosporin A 16 mg/kg/d, were in the range of those obtained with standard-dose daunorubicin in MDR1- cells (p=n.s.). In summary, an idarubicin plus short-course cyclosporin A combination could be considered for the management of MDR1+ leukemias, where it may represent a more effective and less toxic option than daunorubicin plus continuous infusion cyclosporin A.
Chiodini
B
B
Divisione di Ematologia, Ospedali Riuniti, Bergamo, Italy.
Bassan
R
R
Barbui
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D003630:Daunorubicin / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D015255:Idarubicin; D003630:Daunorubicin