Uptake and intracellular distribution of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells

Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl m etabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxo rubicin-resistant P388 cells. Also discussed are the differences in the mec hanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was ab out 80 times as potent as amrubicin, and about 2 times more potent than dox orubicin in a I-h drug exposure growth-inhibition test, A clear cross-resis tance was observed to both amrubicin and amrubicinol in doxorubicin-resista nt P388 cells, though the resistance index was lower for amrubicin. The int racellular concentration of amrubicinol was about 6 times and 2 times highe r than those of amrubicin and doxorubicin, respectively. Compared to doxoru bicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-in hibiting activity and the cellular level of amrubicin and amrubicinol in P3 88 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubici n was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.