CHARACTERIZATION AND MODULATION OF DRUG TRANSPORT KINETICS IN K562 CL.6 DAUNORUBICIN-RESISTANT CELL-LINE

The effects of cyclosporin A (CSA) and cellular energy depletion on da unorubicin (DAU) transport kinetics were investigated in a human eryth roid leukaemia cell line K562 c1.6 selected for resistance to daunorub icin. K562 c1.6/DAU resistant cells displayed high levels of P-glycopr otein and a high level of multidrug resistance against several antitum our drugs. The resistance factors of K562 c1.6/DAU cells to DAU, doxor ubicin, vinblastine and etoposide were 106, 114, 85 and 13 respectivel y. A 16-fold decrease (P<0.01, n=8) in DAU accumulation and a 4-fold i ncrease (P<0.001, n=8)in DAU efflux were shown in the resistant cells when compared to K562 c1.6 drug-sensitive parental cells. K562 c1.6/DA U cells were also shown to reach a DAU saturation level (SL) 8-fold fa ster (P<0.001, n=8) than the parental cells. Addition of CSA to the re sistant cells led to a dose-dependent increase in cellular DAU retenti on, while no such effect was observed in the sensitive cells by the in troduction of CSA. Resistance to the antitumour drugs could be reduced to various extents by CSA. The patterns of changes and modulations of DAU transport kinetics, as well as chemosensitivity in K562 c1.6/DAU cells were found to be similar to a vinblastine-resistant leukaemia ce ll line CEM/VLB(100). However, K562 c1.6/DAU cells were more resistant to DAU, doxorubicin and etoposide than the CEM/VLB(100) cells. An inc rease in DAU accumulation, intracellular SL and the time to reach 90% saturation level (SL90), and a decrease in DAU efflux in the resistant but not the sensitive cells were found in response to ATP depletion b y sodium azide. These effects could be completely reversed by addition of glucose. Our results suggest that the presence of an energy efflux ing mechanism responsible for the decreased drug accumulation and enha nced drug efflux may make a major contribution to the mechanism of res istance in K562 c1.6/DAU resistant cells.