Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells

Amrubicin, a completely synthetic 9-aminoanthracycline derivative, was prev iously shown to have potent antitumor activities against various human tumo r xenografts, In this study, the irt vitro activities of amrubicin and its major metabolite, amrubicinol, were examined using 17 human tumor cell line s. Amrubicinol was 5 to 54 times more potent than amrubicin, and as potent as doxorubicin, in inhibiting the growth of the cells following 3-day conti nuous drug exposure. Amrubicinol closely resembled doxorubicin in its profi le of activities on the 17 human tumor cell lines. Cells were incubated wit h the drugs for 1 h, and the intracellular drug concentration and cell grow th inhibition after 3 days were determined. Amrubicinol attained similar in tracellular concentrations at lower medium concentrations compared to amrub icin, and the intracellular concentration of amrubicinol necessary to produ ce 50% cell growth inhibition was 3 to 8 times lower than that of amrubicin in 4 cell lines tested. Amrubicinol has a higher activity level inside the cells than does amrubicin, When cells were incubated with amrubicin for 5 h, a substantial amount of amrubicinol, more than 9% of that of amrubicin, was found in cells in 4 of the 8 cell lines tested. Amrubicinol may contrib ute to the in vitro growth-inhibitory effect of amrubicin on these cells. T he results suggest that amrubicinol prays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.