CELL-CYCLE DEPENDENT UPTAKE AND RELEASE OF ANTHRACYCLINE BY DRUG-RESISTANT AND DRUG-SENSITIVE HUMAN LEUKEMIC K562 CELLS

The appearance of cellular resistance to antitumor drugs is a major pr oblem in cancer chemotherapy. This results from the overexpression of the mdr 1 gene which encodes the 170 kDa P-glycoprotein or multidrug t ransporter. The uptake and release of 4'-O-tetrahydropyranyladriamycin by drug-sensitive and drug-resistant K562 cells in the different phas e of the cycle have been determined. Synchronized cells were obtained by centrifugal elutriation. The kinetics, as well as the amount of dru g intercalated inside the nucleus and free in the cytoplasm, have been determined using a spectrofluorometric method that we have developed and that does not compromise cell viability. The kinetics of active ef flux of the drug under the effect of P-glycoprotein has been determine d. We have calculated that the number of 4'-O-tetrahydropyranyladriamy cin molecules, which are actively effluxed per cell and per second, is constant whatever the cell cycle phase.