Preclinical and phase I trials of topoisomerase I inhibitors

A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effectiv...

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Published in:Cancer chemotherapy and pharmacology 1994-01, Vol.34 (S1), p.S41-S45
Main Authors: VON HOFF, D. D, BURRIS, H. A, ECKARDT, J, ROTHENBERG, M, FIELDS, S. M, SHIH-FONG CHEN, KUHN, J. G
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - toxicity
Biological and medical sciences
Camptothecin - analogs & derivatives
Camptothecin - toxicity
Cell Line
Chemotherapy
Female
Humans
Indoles - toxicity
Irinotecan
Male
Medical sciences
Neoplasms - drug therapy
Pharmacology. Drug treatments
Pyridines - toxicity
Topoisomerase I Inhibitors
Topotecan
Tumor Cells, Cultured
Tumor Stem Cell Assay
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Summary:A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
ISSN:0344-5704
1432-0843
DOI:10.1007/BF00684862