摘要：

The mechanism of a previously reported decreased accumulation of daunomycin in resistant compared to wild-type Ehrlich ascites tumor cells was investigated in vitro. Several findings indicated an active extrusion of daunomycin from resistant cells: (1) Over a certain range of daunomycin concentrations, the accumulation was considerably higher in isolated nuclei from resistant cells; than in the corresponding whole cells 2) The distribution ratio at steady state of daunomycin in resistant whole cells to that in the medium increased with concentration, in contrast to a decrease for isolated resistant nuclei. (3) Accumulation of daunomycin in resistant cells was enhanced by structural analogs ( N- acetyldaunomycin and daunorubicinol) and by metabolic inhibitors (2-deoxyglucose and iodoacetate). In wild-type cells the accumulation of daunomycin was also increased by 2-deoxyglucose, suggesting an active extrusion of daunomycin from these cells too. The initial rate of net daunomycin uptake was lower in resistant than in wild-type cells, and the decreased accumulation in resistant cells may be due either to a higher rate of active efflux, a lower rate of influx (in the presence of active efflux), or both. The nuclear binding capacity for daunomycin was about the same in the two cell types. Vincristine and vinblastine increased the accumulation of daunomycin in resistant cells. Together with previous findings of reciprocal cross-resistance between daunomycin and the vinca alkaloids, and a decreased accumulation of daunomycin in cells selected for resistance to vincristine and vinblastine, this effect suggests that these drugs are transported by the same extrusion mechanism as daunomycin.

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