Abstract
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.
Current Medicinal Chemistry
Title: Preclinical Evaluation of New Anthracyclines
Volume: 8 Issue: 1
Author(s): G. Pratesi and S. V. Monestiroli
Affiliation:
Abstract: 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.
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Cite this article as:
Pratesi G. and Monestiroli V. S., Preclinical Evaluation of New Anthracyclines, Current Medicinal Chemistry 2001; 8 (1) . https://dx.doi.org/10.2174/0929867013373949
DOI https://dx.doi.org/10.2174/0929867013373949 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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