Effect of cyclosporin A on daunorubicin accumulation in multidrug-resistant P388 leukemia cells measured by real-time flow cytometry
article
We investigated the mode of action of cyclosporin A (Cy-A) as a modifier of multidrug resistance in P388 mouse leukemia cells. A fluorescence-activated flow cytometer (FCM) was modified with a flow-through cuvette to allow continuous on-line monitoring of daunorubicin uptake in vitro. The addition of Cy-A to multidrug-resistant P388/R cells at steady-state daunorubicin uptake, led to a dose-dependent increase in cellular daunorubicin accumulation, as measured by FCM and high-performance liquid chromatography (HPLC). A linear relationship was found between the daunorubicin concentration in the incubation medium and the Cy-A concentration required for optimal stimulation of cellular anthracycline accumulation. The results of a cytotoxicity assay indicated that Cy-A completely restored the chemosensitivity of the P388/R cells. Intracellular Cy-A measurements in P388/S and P388/R cells showed that P388/R cells accumulated significantly less Cy-A than P388/S cells. Relatively high daunorubicin concentrations could not restore that accumulation defect. These results suggest that Cy-A promotes cellular anthracycline accumulation by competing for an outward drug-transport system that operates in multidrug-resistant cells.
Chemicals/CAS: cyclosporin A, 59865-13-3, 63798-73-2; daunorubicin, 12707-28-7, 20830-81-3, 23541-50-6; Cyclosporins; Daunorubicin, 20830-81-3
Chemicals/CAS: cyclosporin A, 59865-13-3, 63798-73-2; daunorubicin, 12707-28-7, 20830-81-3, 23541-50-6; Cyclosporins; Daunorubicin, 20830-81-3
Topics
cyclosporin adaunorubicinanimal cellcancer chemotherapycell culturedrug monitoringdrug resistanceflow cytometryhigh performance liquid chromatographymousenonhumanpriority journalAnimalChromatography, High Pressure LiquidCyclosporinsDaunorubicinDose-Response Relationship, DrugDrug InteractionsDrug ResistanceFlow CytometryLasersLeukemia P388Leukemia, ExperimentalMiceRadioimmunoassayTumor Cells, Cultured
TNO Identifier
230881
ISSN
03445704
Source
Cancer Chemotherapy and Pharmacology, 23(5), pp. 296-300.
Pages
296-300
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