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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Comparison of the membrane transport of anthracycline derivatives in drug-resistant and drug-sensitive K562 cells.

One of the phenotypes of multidrug resistance is characterized by a decrease in the intracellular concentration of drug in resistant cells as compared to sensitive cells. This is correlated with the presence in the membrane of resistant cells of a 150-180-kDa glycoprotein, P-glycoprotein, responsible for an active efflux of the drug. The fluorescence emission spectra from anthracycline-treated cells suspended in buffer have been used to compare the membrane transport of five anthracycline derivatives: adriamycin, daunorubucin, 4'-o-tetrahydropyranyladriamycin, carminomycin and aclacinomycin in drug-sensitive and drug-resistant K562 cells. The initial rate of uptake of these five drugs has been measured as a function of the extracellular pH, pHe. The data show that the uptake occurs through free permeation of the neutral form of the drug. For each drug an influx coefficient kpHe, characteristic of the drug and of the cell type has been defined and calculated: k+(7.2) = V+/[D]e.n where V+ and [D]e are the initial rate of uptake and the concentration of drug in the medium at pHe = 7.2 respectively and n is the number of cells. This coefficient is characteristic of a passive diffusion of the neutral form of the drug through the lipid bilayer. Efflux coefficients k-(7.2)- at pHi = 7.2 (the intracellular pH value) have also been calculated. In the case of sensitive cells, k+(7.2) and k-(7.2)- are equal. For resistant cells, the efflux coefficient is composed of two terms: (a) (k-)p corresponding to the passive diffusion of the neutral form of the drug and (k-)p = k+; (b) (k-)a corresponding to an active efflux mediated by the P-glycoprotein. Our data suggest that the anthracycline derivatives efflux actively in the neutral form.[1]


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