Related Experiment Videos
Topotecan in chronic lymphocytic leukemia
S O'Brien1, H Kantarjian, A Ellis
1Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer
|March 1, 1995
Summary
Topotecan did not show efficacy in chronic lymphocytic leukemia (CLL) patients, despite in vitro DNA-protein cross-linking. Further research is needed to understand its limited clinical effect in CLL.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Topotecan targets topoisomerase I (Topo I), stabilizing DNA-topo1 complexes for cell death.
- Elevated Topo I levels in lymphocytes of chronic lymphocytic leukemia (CLL) patients suggested topotecan as a potential therapeutic agent.
Purpose of the Study:
- To assess the clinical efficacy of topotecan in patients with chronic lymphocytic leukemia (CLL).
- To measure DNA-protein cross-linking after topotecan exposure to correlate anti-CLL effects with this biomarker.
Main Methods:
- Twelve CLL patients, pretreated with fludarabine and/or chlorambucil, received topotecan (2 mg/m2 daily for 5 days, monthly).
- In vitro topotecan exposure (2 microM) of patient cells and measurement of DNA-protein cross-linking.
- Assessment of circulating cell DNA-protein cross-linking post-first dose.
Main Results:
- No patient (0-27% CI) responded to topotecan therapy.
- In vitro, topotecan induced 2-7.5 fold increase in DNA-protein cross-linking.
- In vivo, only 2 of 8 patients showed increased cross-linking in circulating cells, correlating with lack of clinical effect.
Conclusions:
- Topotecan exposure in vitro showed detectable protein-DNA cross-linking in CLL cells.
- This effect was not observed in patients receiving a clinical dose of topotecan.
- No remissions were observed in the 12 treated CLL patients.