Intracellular uptake, retention and cytotoxic effect of adriamycin combined with hyperthermia in vitro.

The intracellular uptake, retention and cytotoxic effect of adriamycin (ADR) were investigated by a flow cytometry technique with NIH 3T3 cells. The intracellular uptake and cytotoxic effect of ADR increased as a function of exposure time and external drug concentration at 37 degrees. A good correlation was found between eventual survival and intracellular ADR uptake. The intracellular uptake and cytotoxic effect of ADR increased with increasing temperature and were shown to be functions of both incubation time and temperature. The intracellular uptake and cytotoxic effect of ADR were increased even at 39 degrees and 41 degrees, temperatures which had no effect on the viability of cells. The combination of hyperthermia (43 degrees) and ADR showed a synergistic effect. It was found that the cytotoxic effects of ADR in combination with various levels of hyperthermia were stronger than those which would be predicted from the intracellular ADR uptake at 37 degrees. The degree of enhancement was temperature-dependent. Since the efflux of intracellular ADR was the same with or without hyperthermia, the increased intracellular ADR uptake caused by elevated temperature was considered to result from an increase in influx.