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Complex response of breast epithelial cell lines to topoisomerase inhibitors.

Publication ,  Journal Article
Davis, PL; Shaiu, WL; Scott, GL; Iglehart, JD; Hsieh, TS; Marks, JR
Published in: Anticancer Res
1998

The topoisomerase inhibitors, camptothecin and etoposide target the activity of topoisomerase I and II respectively. These agents, or their analogues, are undergoing clinical trials for the treatment of metastatic breast cancer. In this study, we examined the response of eight breast epithelial cell lines, including six lines derived from breast cancers and two immortalized normal epithelial lines to camptothecin and etoposide. The lines varied by 700 fold in their sensitivity to the growth inhibiting effects of camptothecin and 30 fold in their response to etoposide. The BT474 line was the most resistant to both agents. The other cell lines did not have uniform sensitivity to both drugs, i.e., some lines were sensitive to one drug but relatively resistant to the other. A variety of parameters in these lines were analyzed to elucidate mechanisms of resistance including S phase, doubling time, expression and activity of topoisomerase I and II, expression of mdr-1, p53 status, cell cycle arrest, level of apoptosis, and expression of the apoptotic proteins Bcl-2 and Bax. We found that low levels of the topo I protein and its enzymatic activity were associated with increased resistance to camptothecin. This was not true for topo II activity and etoposide. Increased apoptotic responses were generally observed in cell lines that were sensitive to etoposide and this correlated with low ratios of Bcl-2/Bax protein. No single parameter was entirely predictive of response. However, the BT474 line displayed a series of characteristics including slow growth, the presence of mutant p53, low topo I activity, and a high Bcl-2/Bax ratio which together likely contributed to the resistance of this line to both etoposide and camptothecin.

Duke Scholars

Published In

Anticancer Res

ISSN

0250-7005

Publication Date

1998

Volume

18

Issue

4C

Start / End Page

2919 / 2932

Location

Greece

Related Subject Headings

  • Tumor Cells, Cultured
  • Topoisomerase II Inhibitors
  • Topoisomerase I Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Oncology & Carcinogenesis
  • Humans
  • Female
  • Etoposide
  • Epithelium
  • Enzyme Inhibitors
 

Citation

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Davis, P. L., Shaiu, W. L., Scott, G. L., Iglehart, J. D., Hsieh, T. S., & Marks, J. R. (1998). Complex response of breast epithelial cell lines to topoisomerase inhibitors. Anticancer Res, 18(4C), 2919–2932.
Davis, P. L., W. L. Shaiu, G. L. Scott, J. D. Iglehart, T. S. Hsieh, and J. R. Marks. “Complex response of breast epithelial cell lines to topoisomerase inhibitors.Anticancer Res 18, no. 4C (1998): 2919–32.
Davis PL, Shaiu WL, Scott GL, Iglehart JD, Hsieh TS, Marks JR. Complex response of breast epithelial cell lines to topoisomerase inhibitors. Anticancer Res. 1998;18(4C):2919–32.
Davis, P. L., et al. “Complex response of breast epithelial cell lines to topoisomerase inhibitors.Anticancer Res, vol. 18, no. 4C, 1998, pp. 2919–32.
Davis PL, Shaiu WL, Scott GL, Iglehart JD, Hsieh TS, Marks JR. Complex response of breast epithelial cell lines to topoisomerase inhibitors. Anticancer Res. 1998;18(4C):2919–2932.

Published In

Anticancer Res

ISSN

0250-7005

Publication Date

1998

Volume

18

Issue

4C

Start / End Page

2919 / 2932

Location

Greece

Related Subject Headings

  • Tumor Cells, Cultured
  • Topoisomerase II Inhibitors
  • Topoisomerase I Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Oncology & Carcinogenesis
  • Humans
  • Female
  • Etoposide
  • Epithelium
  • Enzyme Inhibitors