COMPARISON OF IDARUBICIN AND DAUNORUBICIN AND THEIR MAIN METABOLITES REGARDING INTRACELLULAR UPTAKE AND EFFECT ON SENSITIVE AND MULTIDRUG-RESISTANT HL-60 CELLS

To study the effect of the main metabolites on the cytotoxic effect of daunorubicin and idarubicin in human HL-60 cells, drug-sensitive and multidrug-resistant HL60 cells were incubated with idarubicin and daun orubicin and their metabolites idarubicinol and daunorubicinol over a wide range of concentrations. The intracellular uptake of the drugs wa s determined by photofluorometry, and the cytotoxic effect in vitro wa s determined by a bioluminescence assay of intracellular adenosine tri phosphate (ATP) after 4 days of culture in liquid medium, The effect o f intracellular drugs was calculated from the incubation-concentration versus intracellular-uptake and cytotoxic-effect curves. The intracel lular uptake of idarubicin was 6 times that of daunorubicin in drug-se nsitive cells and 25 times higher in resistant cells. For idarubicinol as compared with daunorubicinol the corresponding factors were 25 and 7, respectively. As compared with the parent substances, the uptake o f idarubicinol and daunorubicinol was 16% and 4%, respectively, in sen sitive cells and 40% and >100%, respectively, in resistant cells. An i ntracellular concentration of 0.5 nmol/mg protein of both parent subst ances caused a 50% growth inhibition in drug-sensitive cells as compar ed with 10 nmol/mg protein for drug-resistant cells. For the metabolit es an intracellular concentration of 0.4 nmol/mg protein of idarubicin ol and 2.0 nmol/mg protein of daunorubicinol was required to inhibit c ells' growth by 50% in drug-sensitive HL60 cells. In the resistant HL6 0 cells the corresponding values were 30 nmol/mg protein for idarubici nol and 40 nmol/mg protein for daunorubicinol. These results confirm t hat idarubicinol may significantly contribute to the clinical effect o f idarubicin. However, in combination with previous results that have shown low intracellular concentrations of the metabolites in vivo, it appears that the pharmacokinetic properties of the mother substances p rovide the major explanation for the clinical effect of idarubicin.