amrubicin and Leukemia-P388

Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 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 doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cell Division; Drug Resistance, Neoplasm; Leukemia P388; Mice; Tumor Cells, Cultured

The tissue distribution of a novel antitumor anthracycline antibiotic, amrubicin, was studied using seven human tumor xenografts implanted into nude mice, in order to identify the principal factors determining its therapeutic efficacy. We found a good correlation between the level of the metabolite amrubicinol in the tumor and the in vivo efficacy. High metabolic activity of amrubicin to amrubicinol was detected in tumor tissue homogenates, especially in cell lines highly sensitive to amrubicin in vivo. In contrast to amrubicin, the administration of amrubicinol showed less tumor-selective toxicity in these human tumor xenograft models. These data indicate that the tumor-selective metabolism of amrubicin to amrubicinol resulted in a tumor-selective disposition of amrubicinol, leading to good efficacy in in vivo experimental therapeutic models.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Biotransformation; Breast Neoplasms; Female; Humans; Leukemia P388; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Nude; Stomach Neoplasms; Structure-Activity Relationship; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured

Currently many antitumor candidate compounds are under clinical trials in Japan. These compounds include synthetic compounds and natural products and their chemical modifiers. Concerning synthetics, fluoropyrimidines and other antimetabolites, cisplatin analogues and other compounds are in phase I or II trials. As for the natural products, antitumor antibiotics including anthracyclines, bleomycin analogue and others and chemically modified plant products are major candidate compounds under phase I or II trials. We are expecting to develop clinically useful drugs among these compounds which have been in clinical trials currently in Japan.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Bleomycin; Cisplatin; Leukemia P388; Lung Neoplasms; Melanoma, Experimental; Mice; Oxazines