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The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells.

AbstractPURPOSE:
To determine the in vitro drug sensitivity of two non-small-cell lung cancer cell lines after treatment with the novel lipophilic camptothecin derivative, 7- tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), to determine if topoisomerase I protein levels decrease after treatment with DB-67, and to assess the duration and extent of topoisomerase I modulation after DB-67 exposure, in order to provide information about drug resistance that may be useful in determining an appropriate dosing schedule for DB-67.
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.
AuthorsAimee K Bence, Cynthia A Mattingly, Thomas G Burke, Val R Adams
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 54 Issue 4 Pg. 354-60 (Oct 2004) ISSN: 0344-5704 [Print] Germany
PMID15197485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Organosilicon Compounds
  • 7-tert-butyldimethylsilyl-10-hydroxycamptothecin
  • DNA Topoisomerases, Type I
  • Camptothecin
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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