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PMID: 2706734 Published · ppublish English Journal Article

Effect of cyclosporin A on daunorubicin accumulation in multidrug-resistant P388 leukemia cells measured by real-time flow cytometry.

Cancer chemotherapy and pharmacology ·Vol. 23 ·No. 5 ·1989-00-00 ·Pages 296-300

Nooter K, Oostrum R, Jonker R, van Dekken H, Stokdijk W, van den Engh G

Abstract

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.

MeSH Terms
Animals Chromatography, High Pressure Liquid Cyclosporins/analysis,pharmacokinetics,pharmacology Daunorubicin/analysis,pharmacokinetics,toxicity Dose-Response Relationship, Drug Drug Interactions Drug Resistance Flow Cytometry Lasers Leukemia P388/drug therapy,metabolism Leukemia, Experimental/metabolism Mice Radioimmunoassay Tumor Cells, Cultured
Chemicals
Cyclosporins Daunorubicin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Nooter K
Radiobiological Institute TNO, Rijswijk, The Netherlands.
Oostrum R
Jonker R
van Dekken H
Stokdijk W
van den Engh G
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Article Info
Journal
Cancer chemotherapy and pharmacology
Abbr.
Cancer Chemother Pharmacol
ISSN
0344-5704
DOI
10.1007/BF00292407
Published
1989-00-00
Pages
296-300
Language
English
Region
Germany
NLM ID
7806519
Subset
IM
External Links
PubMed source DOI: 10.1007/BF00292407 View journal details
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