Preclinical Evaluation of New Anthracyclines

We designed a screening system for new anthracyclines totally based on human tumor material. In the first step of the system, the relative cytotoxicity versus doxorubicin of all new compounds is investigated in a panel of human tumor cell lines, well characterized for resistance factors and p53 status. Only a few analogs are selected through this step for further evaluation. The second step is aimed to investigate the therapeutic efficacy and the tolerability of the analog, which is compared to doxorubicin in a series of human tumor xenografts selected for presenting natural or acquired (by known mechanisms) resistance to the parent drug. Cardiotoxicity in mice is also studied. Cellular and molecular pharmacology studies are also considered. The results of a series of disaccharide anthracycline analogs screened by the system are presented. An analog of the series, MEN 10755, was selected for clinical investigation and is currently evaluated in Phase I trials. The ability of human tumor xenografts to predict the clinical efficacy of anthracycline analogs is also discussed.