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The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells.
Cancer Chemother Pharmacol. 2004 Oct; 54(4):354-60.CC

Abstract

PURPOSE

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.

Authors+Show Affiliations

Division Pharmacy Practice and Science, 202 College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15197485

Citation

Bence, Aimee K., et al. "The Effect of DB-67, a Lipophilic Camptothecin Derivative, On Topoisomerase I Levels in Non-small-cell Lung Cancer Cells." Cancer Chemotherapy and Pharmacology, vol. 54, no. 4, 2004, pp. 354-60.
Bence AK, Mattingly CA, Burke TG, et al. The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells. Cancer Chemother Pharmacol. 2004;54(4):354-60.
Bence, A. K., Mattingly, C. A., Burke, T. G., & Adams, V. R. (2004). The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells. Cancer Chemotherapy and Pharmacology, 54(4), 354-60.
Bence AK, et al. The Effect of DB-67, a Lipophilic Camptothecin Derivative, On Topoisomerase I Levels in Non-small-cell Lung Cancer Cells. Cancer Chemother Pharmacol. 2004;54(4):354-60. PubMed PMID: 15197485.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells. AU - Bence,Aimee K, AU - Mattingly,Cynthia A, AU - Burke,Thomas G, AU - Adams,Val R, Y1 - 2004/06/12/ PY - 2003/06/30/received PY - 2004/02/26/accepted PY - 2004/6/16/pubmed PY - 2004/10/20/medline PY - 2004/6/16/entrez SP - 354 EP - 60 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother Pharmacol VL - 54 IS - 4 N2 - PURPOSE: 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. SN - 0344-5704 UR - https://www.unboundmedicine.com/medline/citation/15197485/The_effect_of_DB_67_a_lipophilic_camptothecin_derivative_on_topoisomerase_I_levels_in_non_small_cell_lung_cancer_cells_ L2 - https://dx.doi.org/10.1007/s00280-004-0804-3 DB - PRIME DP - Unbound Medicine ER -