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m-AMSA as a probe for transport phenomena associated with anthracycline resistance
Abstract:
Kinetics of transport of the acridine derivative 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) were examined in P388 murine leukemia cells and in P388/ADR, a subline selected for adriamycin resistance and cross-resistant to a variety of drugs including m-AMSA. Compared with the drug-responsive parent cell line, P388/ADR cells showed impaired accumulation of m-AMSA and an enhanced rate of drug exodus. Competition studies demonstrated structural specificity of the outward transport process. There was a low degree of intracellular m-AMSA binding, and steady-state drug levels were reached in less than 1 min. These results suggest that m-AMSA will be a useful probe for studying transport systems associated with anthracycline resistance.
Insights
Drug resistance in leukemia cells involves altered transport. P388/ADR cells exhibit reduced accumulation and faster efflux of 4
Area of Science:
- Pharmacology and Toxicology
- Cancer Cell Biology
- Drug Resistance Mechanisms
Background:
- Adriamycin resistance in cancer cells often confers cross-resistance to other drugs.
- Understanding drug transport kinetics is crucial for overcoming multidrug resistance (MDR).
Purpose of the Study:
- To investigate the transport kinetics of the acridine derivative 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA).
- To compare m-AMSA transport in drug-sensitive P388 murine leukemia cells versus adriamycin-resistant P388/ADR cells.
Main Methods:
- Cellular accumulation and efflux studies of m-AMSA in P388 and P388/ADR cells.
- Competition assays to assess the structural specificity of drug efflux.
- Measurement of intracellular m-AMSA binding and steady-state drug levels.
Main Results:
- P388/ADR cells demonstrated significantly impaired m-AMSA accumulation compared to P388 cells.
- An enhanced rate of m-AMSA exodus was observed in the resistant P388/ADR subline.
- Competition studies indicated structural specificity in the outward drug transport process.
Conclusions:
- Drug resistance in P388/ADR cells is associated with defective m-AMSA uptake and increased drug efflux.
- m-AMSA transport is structurally specific, suggesting involvement of dedicated transport systems.
- m-AMSA serves as a valuable molecular probe for investigating transport mechanisms linked to anthracycline resistance.