Idarubicin Activity Against Multidrug-Resistant (mdr-1+) Cells is Increased by Cyclosporin A
Multidrug resistance related to functional overexpression of P-170 glycoprotein (mdr-1 gene) is often responsible for treatment failure in acute leukaemia. Attempts to restore drug sensitivity with revertants and less vulnerable drugs are underway. We compared the ability of cyclosporin A to modulate mdr-1 resistance of T-lymphoblastic CEM cells to daunorubicin and idarubicin. To obtain clinically useful informations, experimental conditions reproduced partially in vivo pharmacology (drug peak plasma levels, alcohol metabolites, exposure times) of a single intravenous bolus with daunorubicin 45 mg/m2 or idarubicin 10–12 mg/m2, plus cyclosporin A 16 mg/kg/d given as continuous infusion (List schedule). Study methods were cytofluorimetry for detection of anthracycline early uptake, retention and pro-apoptotic effects (binding to fluoresceinated annexin V) at the single cell level, and the standard MTT growth inhibition assay for cytotoxicity. The results showed greater drug uptake/retention and apoptotic rates with idarubicin than with daunorubicin, with a further increase by cyclosporin A. MTT results were in favour of idarubicin with or without cyclosporin A, and greatly influenced by cyclosporin A itself. Altogether, study results in mdr-1+ cells with idarubicin/idarubicinol at 100/20 ng/ml, corresponding to levels achievable in vivo with a single idarubicin dose ≥ 12 mg/m2, were in the range of those obtained with standard-dose daunorubicin in mdr1-cells. These findings underscore the potential usefulness of an idarubicin plus cyclosporin A combination in mdr-1+ leukaemias, and prompt further studies on associations with other modulators of P-170 functional activity.
KeywordsAcute Myeloid Leukemia High Drug Concentration Leukaemic Cell Single Intravenous Bolus Alcohol Metabolite
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- 1.D’Incalci M, Capranico G, Giaccone G, Zunino F, Garattini S (1993) DNA topoisomerase inhibitors. In: Pinedo HM, Longo DL, Chabner BA (eds) Cancer Chemotherapy and Biological response Modifiers Annual 14. Elsevier, Amsterdam, pp 61–85Google Scholar
- 8.Ross D, Tong Y, Cornblatt B (1993) Idarubicin (IDA) is less vulnerable to transport-mediated multidrug resistance (MDR) than its metabolite idarubicinol (IDAoI) or daunorubicin (DNR). Blood 82 (Suppl 1): 257aGoogle Scholar
- 9.Kuffel MJ, Reid JM,Ames MM (1992) Anthracydines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture. Cancer Chemother Pharmacol 30: 51–57Google Scholar
- 12.Koopman G, Reutelingsperger CPM, Kuijten GAM et al. (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84: 1415–1420Google Scholar
- 13.Kokenberg E, Sonneveld P, Delwel R, Sizoo W, Hagenbeeck A, Löwenberg B (1988) In vivo uptake of daunorubicin by acute myeloid leukemia AML) cells measured by flow cytometry. Leukemia 2: 511–517Google Scholar
- 15.Grey MR, Burgess R, Fisher A, Liu Yin JA (1996) Idarubicin is superior to daunorubicin when used with the multidrug resistance modifier, PSC 833, in acute myeloid leukaemia. Br J Haematol 93 (Suppl 1): 64aGoogle Scholar
- 16.Ito C, Ribeiro RC, Behm FG, Raimondi SC, Pui CH, Campana D (1996) Cyclosporine A induces apoptosis in childhood acute lymphoblastic leukemia cells. Blood 88 (Suppl 1): 261-IaGoogle Scholar