TRANSPORT MECHANISMS OF ANTHRACYCLINE DERIVATIVES IN HUMAN LEUKEMIA-CELL LINES - UPTAKE OF PIRARUBICIN, DAUNORUBICIN AND DOXORUBICIN BY K562 AND MULTIDRUG-RESISTANT K562 ADM CELLS/

We studied the uptake mechanisms of anthracycline derivatives, pirarub icin (THP), daunorubicin (DNR) and doxorubicin (ADR), in K562 and mult idrug-resistant K562/ADM cells, which overexpress a multidrug efflux p ump P-glycoprotein (P-gp). The uptake of THP, DNR and ADR by K562 or K 562/ADM cells was time-, temperature- and concentration-dependent. The THP and ADR uptake by the parental cells was not affected by treatmen t with 4 mM 2,4-dinitrophenol (DNP) alone or DNP plus a P-gp specific inhibitor, cyclosporin A (CBA, 10 mu M), while the DNR uptake in the D NP treatment group was significantly greater than that in the control group. There was no difference in the uptake of THP between DNP-pretre ated K562 cells and DNP plus CyA-pretreated K562/ADM cells. The uptake of DNR or ADR was almost equal in both types of cell treated with DNP alone. Every kinetic constant for THP, DNR and ADR uptake by the sens itive cells was approximately equal to that in the resistant cells, re spectively, under the above conditions. THP uptake was noncompetitivel y inhibited and stimulated on simultaneous treatment and preloading, r espectively, of DNR or ADR in each type of cell. ADR showed noncompeti tive inhibition of DNR uptake by either type of cell. Therefore, it wa s suggested that a common carrier-mediated transport system was involv ed in the uptake of THP, DNR and ADR, and that their binding sites in the carrier might be different from one another in both K562 and K562/ ADM cells.