Relationship between the intracellular accumulation of anthracyclines and effectiveness in vitro and in vivo.

The relationship between accumulation, retention and cytotoxicity of various anthracyclines was investigated in Friend leukaemia cells growing in vitro. By comparison to that of adriamycin (ADM) and epi-adriamycin (Epi-ADM), the uptake of demethoxy-daunorubicin (DM-DNR) and THP-adriamycin (THP-ADM) is a rapid process. In cells exposed to DM-DNR or THP-ADM, a 50% accumulation is reached in less than 2 min, whereas 80 min and up to 4 hours are needed for epi-ADM or ADM, respectively. More than 95% of these anthracyclines are accumulated and retained in the nuclear fraction. Following a short cell exposure, the intracellular concentrations of the rapidly incorporated drugs (DM-DNR or THP-ADM) decrease with the cell density. After cell exposure to one of these drugs followed by growth in drug-free medium, the cytotoxic activity is related to the ease with which the anthracycline accumulates in cells. Since the pharmacological properties of these anthracyclines differ, and because cytotoxic activity correlates with these properties, plasma and intracellular concentrations of ADM and THP-ADM were studied after intravenous administration in leukaemic and non-leukaemic patients with various white blood cell concentrations. Since the pharmacokinetic studies in vivo correlated to in vitro parameters, it is concluded that administration modalities have to be determined, adapted to each patient, and considered differently according to the anthracycline used.