Comparative evaluation of the intracellular accumulation and DNA binding of idarubicin and daunorubicin in sensitive and multidrug-resistant human leukaemia K562 cells.

BACKGROUND

Idarubicin is a new anthracycline, more potent in in vitro models than the common anthracyclines doxorubicin and daunorubicin. The intracellular accumulation and DNA binding of daunorubicin and idarubicin have been studied in human leukaemia K562 cells and their doxorubicin-resistant variant, which presents all features of multidrug resistance.

METHODS

This was achieved by measuring the decrease of total drug fluorescence during short-term incubation of cell suspensions, directly in the cuvette of a spectrofluorometer; this quenching is due to intercalation of the drug into DNA and represents an evaluation of the active intracellular concentration of the drugs.

RESULTS

Accumulation of both anthracyclines was reduced in resistant cells when compared to sensitive ones. Accumulation of idarubicin was significantly higher than that of daunorubicin in both cell types. The difference in anthracycline accumulation between sensitive and resistant cells was lower for idarubicin than for daunorubicin. Verapamil increased the accumulation of both anthracyclines in resistant cells, with a more pronounced effect for idarubicin. Preincubation of the cells with either drug did not influence the accumulation of the other one.

CONCLUSION

It has been shown, with this very rapid technique, that the high potency of idarubicin could be explained, at least in part, by its high level of accumulation, both in sensitive and multidrug-resistant leukaemia cells. This is not due to a lack of activity of P-glycoprotein on idarubicin, but rather to an enhanced influx of this drug compared to daunorubicin.