title: Preclinical and phase I trials of topoisomerase I inhibitors.
abstract: 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.
authors.affiliation: University of Texas Health Science Center at San Antonio 78284.
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: J
authors.initials: J
authors.lastname: Eckardt
authors.forename: M
authors.initials: M
authors.lastname: Rothenberg
authors.forename: S M
authors.initials: SM
authors.lastname: Fields
authors.forename: S F
authors.initials: SF
authors.lastname: Chen
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002460:Cell Line; D005260:Female; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D000077146:Irinotecan; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000633:toxicity*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; C081834:intoplicine; D002166:Camptothecin