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Clinical trials with the topoisomerase I inhibitors
H A Burris1, M L Rothenberg, J G Kuhn
1Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX.
Abstract:
Topoisomerase I represents a unique new target that can be exploited for development of new antineoplastic agents. There are now two new topoisomerase I inhibitors that are in early clinical trials that have generated a tremendous amount of interest. Topotecan (SKF 104864-A) is a topoisomerase I inhibitor that has been explored in phase I trials using a variety of dosages and schedules. The dose-limiting toxicity of the agent is neutropenia. Other toxicities include alopecia, very mild nausea and vomiting, anemia, and occasional fever. Responses have already been noted in patients with advanced, refractory ovarian cancer and non--small-cell lung cancer. The drug is currently undergoing intense phase II testing. Irinotecan (CPT-11) is also a topoisomerase I inhibitor, which has already undergone extensive phase I and early phase II clinical testing in both Japan and the United States. Dose-limiting toxicities of the agent have included neutropenia and diarrhea. Responses have been noted in patients with refractory colorectal cancer, non--small-cell lung cancer, lymphoma, ovarian cancer, head and neck cancer, pancreatic cancer, and breast cancer. There is no doubt both of these agents will be important additions to our chemotherapy armamentarium.
Insights
Two novel topoisomerase I inhibitors, Topotecan and Irinotecan, show promise as new antineoplastic agents. Clinical trials indicate efficacy in various cancers, with neutropenia as a primary dose-limiting toxicity.
Area of Science:
- Oncology
- Pharmacology
Background:
- Topoisomerase I is a validated target for novel antineoplastic drug development.
- Two new topoisomerase I inhibitors, Topotecan and Irinotecan, are generating significant interest.
Purpose of the Study:
- To review the early clinical trial data for Topotecan and Irinotecan.
- To assess the efficacy and toxicity profiles of these novel agents.
Main Methods:
- Phase I and early Phase II clinical trials were conducted for both agents.
- Data on dosages, schedules, toxicities, and patient responses were collected.
Main Results:
- Topotecan demonstrated responses in ovarian and non-small-cell lung cancer, with neutropenia as dose-limiting toxicity.
- Irinotecan showed efficacy in colorectal, lung, lymphoma, ovarian, head and neck, pancreatic, and breast cancers, with neutropenia and diarrhea as dose-limiting toxicities.
Conclusions:
- Topotecan and Irinotecan represent promising new additions to the chemotherapy armamentarium.
- Further Phase II testing is underway for Topotecan, while Irinotecan has undergone extensive early-phase trials.