title: Cellular uptake, cytotoxicity, and transport kinetics of anthracyclines in human sensitive and multidrug-resistant K562 cells.
abstract: Multidrug resistance in tumor cells is often associated with the presence of an approximately 170 kDa plasma membrane glycoprotein (Pgp) that acts as a drug-efflux pump and decreases intracellular antitumor drug concentration. We measured the uptake of seven anthracyclines (daunorubicin, doxorubicin, 4'-epi-doxorubicin, 4'-deoxy-doxorubicin, iododoxorubicin, 3'-(3-methoxymorpholino)-doxorubicin (FCE23762) and 4-demethoxy-daunorubicin) into K562 cells sensitive and resistant (K562/DNR) to daunorubicin. The K562/DNR subline expresses Pgp at the membrane surface, whereas its sensitive counterpart does not. Laser flow cytometry was used to quantitate intracellular anthracycline content. Uptake of daunorubicin, doxorubicin, 4'-epi-doxorubicin, and 4'-deoxy-doxorubicin was minimal in the K562/DNR subline as compared to their uptake in sensitive cells. On the contrary, iododoxorubicin, FCE23762, and 4-demethoxy-daunorubicin accumulate to nearly the same extent into sensitive and resistant K562 cells. Growth inhibition data indicated that the resistance factor for iododoxorubicin, FCE23762, and 4-demethoxy-daunorubicin is markedly decreased as compared to the other drugs. Fluorescence measurements were carried out to determine the kinetic parameters associated with the influx and efflux of the drugs into and out of K562 cells. Kinetic data indicated that iododoxorubicin, FCE23762, and 4-demethoxy-daunorubicin are not actively rejected from resistant cells, suggesting that they are poor substrates for Pgp-mediated transport. This observation is related to their ability to overcome the multidrug-resistant phenotype of K562/DNR cells in vitro.
authors.affiliation: Laboratoire de Chimie-Physique des Macromolécules aux Interfaces, Université Libre de Bruxelles, Belgique.
authors.forename: M
authors.initials: M
authors.lastname: Praet
authors.forename: P
authors.initials: P
authors.lastname: Stryckmans
authors.forename: J M
authors.initials: JM
authors.lastname: Ruysschaert
mesh_terms: D018943:Anthracyclines / Q000378:metabolism* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D018943:Anthracyclines