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Preclinical and phase I trials of topoisomerase I inhibitors
D D Von Hoff1, H A Burris, J Eckardt
1University of Texas Health Science Center at San Antonio 78284.
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.
Insights
Continuous exposure to topoisomerase I inhibitors, including topotecan and irinotecan (CPT-11), shows greater efficacy against human tumors. Each drug has unique dose-limiting toxicities and varying clinical responses.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Topoisomerase I inhibitors are a class of anticancer drugs.
- Three agents, topotecan, CPT-11 (irinotecan), and intoplicine, have undergone preclinical and clinical evaluation.
- Understanding their efficacy and toxicity is crucial for optimizing cancer treatment.
Purpose of the Study:
- To compare the efficacy and toxicity of topotecan, CPT-11, and intoplicine.
- To evaluate the impact of drug exposure duration on the effectiveness of these topoisomerase I inhibitors.
- To characterize the pharmacokinetic profiles and dose-limiting toxicities of these agents.
Main Methods:
- In vitro testing using human tumor colony-forming units.
- Phase I clinical pharmacology studies.
- Pharmacokinetic analysis to determine drug half-lives.
Main Results:
- Continuous exposure was more effective than 1-hour exposure for all three compounds in vitro.
- Dose-limiting toxicities varied: neutropenia/thrombocytopenia for topotecan, diarrhea for CPT-11, and hepatotoxicity for intoplicine.
- Clinical responses included marginal responses with topotecan, partial/marginal responses with CPT-11 (notably in colon cancer), and no response with intoplicine.
Conclusions:
- Topoisomerase I inhibitors demonstrate differential efficacy and toxicity profiles.
- CPT-11 (irinotecan) shows particular promise, especially for colon cancer treatment.
- These agents, particularly CPT-11, represent valuable additions to the cancer therapeutic arsenal.