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[Topoisomerase I inhibitor with potential radiosensitizing effect]
Aim:
In search of new drugs which should be theoretically able to modify radiation effects, the topoisomerase I-inhibitor topotecan was identified in November 1996, approval for second-line therapy of ovarian carcinoma was given in Germany.
Material And Method:
This review article describes mechanisms of action, pharmacokinetic, preclinical and recent clinical data on topotecan with and without concomitant radiation therapy.
Results:
Following a 30 min. intravenous bolus, median plasma half-lives between 2 and 3 h. and a total-body clearance of 0.57 l/min/m2 were seen. After oral administration the bioavailability varied between 30 and 35%. Topotecan is able to pass the blood brain barrier. Encouraging clinical results are reported in gastrointestinal tumors, head and neck squamous cell carcinoma, small cell and non-small cell lung cancer, breast cancer, leukemia and pediatric tumors in addition to ovarian carcinoma. Recent studies indicate that topotecan functions as a radiosensitizer and may be applied together with radiation in future trials. In vivo and in vitro experiments revealed a good modulation ofradiation effects of topotecan.
Conclusions:
In experimental and preclinical studies using topotecan both additive and sensitization effects to normal cells and tumor cells were seen by ionizing radiation. Clinical phase II/III trials may preferentially be indicated in non-small cell lung cancer and primary and metastatic brain tumors.
Insights
Topotecan, a topoisomerase I inhibitor, shows promise in modifying radiation effects and has demonstrated encouraging clinical results across various cancers. Further trials are suggested for its use as a radiosensitizer, particularly in lung and brain tumors.
Area of Science:
- Oncology
- Pharmacology
- Radiation Oncology
Background:
- Topoisomerase I inhibitor identified as a potential modulator of radiation effects.
- Topotecan approved in Germany for second-line ovarian carcinoma therapy in 1996.
Purpose of the Study:
- To review mechanisms of action, pharmacokinetics, and clinical data of topotecan.
- To evaluate topotecan's efficacy with and without radiation therapy.
- To explore topotecan's role as a radiosensitizer.
Main Methods:
- Review of existing literature on topotecan.
- Analysis of pharmacokinetic data (half-life, clearance, bioavailability).
- Summary of preclinical and clinical trial results.
Main Results:
- Topotecan exhibits median plasma half-lives of 2-3 hours and a total-body clearance of 0.57 l/min/m2.
- Oral bioavailability ranges from 30-35%; it crosses the blood-brain barrier.
- Encouraging results reported in ovarian, gastrointestinal, lung, breast, leukemia, pediatric, and head and neck cancers.
- Topotecan acts as a radiosensitizer, modulating radiation effects in vitro and in vivo.
Conclusions:
- Topotecan demonstrates additive and sensitization effects with ionizing radiation on both normal and tumor cells.
- Clinical trials are recommended for non-small cell lung cancer and brain tumors.