Abstract | PURPOSE: METHODS: The growth inhibition of the non-small-cell lung cancer cell lines A549 and H460 after exposure to DB-67 was evaluated with the MTS assay. A549 and H460 cells were treated for various times with DB-67 and topoisomerase I levels were determined by western blot analysis. In addition, A549 and H460 cells were treated with DB-67 for 24 h and topoisomerase I levels were determined by western blot analysis daily for 1 week after drug removal. RESULTS:
DB-67 inhibited the growth of both A549 and H460 cells grown in culture; the A549 cells were more resistant to the cytotoxic effects of DB-67 than H460 cells. Notably, A549 cells had approximately one-half the baseline topoisomerase I than H460 cells. Topoisomerase I protein levels significantly decreased after 8-18 h of exposure to DB-67. Both A549 and H460 cells treated with DB-67 for 24 h had only negligible amounts of topoisomerase I at the end of treatment. However, within 24 h of drug removal topoisomerase I levels returned to near baseline levels in both cell lines. CONCLUSIONS: The decrease in topoisomerase I levels caused by DB-67 may represent a mechanism of resistance to this novel camptothecin derivative. Dosing DB-67 once every 48-72 h may maximize the interaction of the drug with topoisomerase I and should be considered as a potential dosing schedule in the preclinical and clinical development of this compound.
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Authors | Aimee K Bence, Cynthia A Mattingly, Thomas G Burke, Val R Adams |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 54
Issue 4
Pg. 354-60
(Oct 2004)
ISSN: 0344-5704 [Print] Germany |
PMID | 15197485
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Organosilicon Compounds
- 7-tert-butyldimethylsilyl-10-hydroxycamptothecin
- DNA Topoisomerases, Type I
- Camptothecin
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Topics |
- Camptothecin
(analogs & derivatives, chemistry, pharmacology)
- Carcinoma, Non-Small-Cell Lung
(enzymology)
- DNA Topoisomerases, Type I
(metabolism)
- Drug Screening Assays, Antitumor
- Humans
- Lung Neoplasms
(enzymology)
- Organosilicon Compounds
(chemistry, pharmacology)
- Time Factors
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