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Modulation of induced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate

  • Original Articles
  • Adriamycin Resistance, Breast Cancer, Tamoxifen, Cell Lines
  • Published:
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Summary

The clinical utility of adriamycin in the treatment of patients with metastatic breast cancer is oftenlimited by the development of drug resistance. It has been recognized that in addition to the development of primary resistance against adriamycin, malignant cells can simultaneously develop cross-resistance to other agents. An adriamycin-resistant human breast cancer cell line (MCF 7Ad) was developed by exposing the parent line (MCF 7) to gradually increasing concentrations of adriamycin while the cells were being grown in monolayer. Using these lines in a clonogenic assay, the relative drug sensitivities to adriamycin, vinblastine, melphalan, 5-fluorouracil and methotrexate were studied. MCF 7Ad was 12.5-fold more resistant to adriamycin than MCF 7 and 500-fold cross-resistant to vinblastine. There was no cross-resistance to melphalan, 5-fluorouracil or methotrexate. The resistance of MCF 7Ad was decreased by simultaneous exposure to tamoxifen (by a factor of 3.33) or perhexiline maleate (by a factor of 7.50). This decreased resistance was evidenced by a shift to the left of the sensitivity curves. However, there was no consistent change in the sensitivity curves of MCF 7. At the selected concentration of tamoxifen and perhexiline maleate, the cloning efficiency of MCF 7 and MCF 7Ad was 80%–90% of control values in medium without tamoxifen, perhexiline maleate or cytotoxic drugs. The resistance of MCF 7Ad to adriamycin was associated with a lower accumulation of [14C]adriamycin than exhibited by the sensitive MCF 7 line. There was no consistent change in [14C]adriamycin accumulation in MCF 7 or MCF 7Ad when tamoxifen was added, but when perhexiline maleate was added the [14C] accumulation increased. These results suggest that the tamoxifen-induced change in MCF 7Ad adriamycin resistance was not due to an increase in the amount of cell-associated adriamycin, but rather to some other mechanism that increased the cytotoxicity of the adriamycin.

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Abbreviations

RPMI 1640:

Roswell Park Memorial Institute medium 1640

FBS:

fetal bovine serum

PBS:

phosphate buffered saline

trypsin-EDTA:

trypsin (w/0.05%) plus ethylenediaminetetraacetic acid (w/0.02%)

IC50 :

concentration of each drug, extrapolated from concentration versus colony formation curve, that inhibits colony formation by 50% as compared to controls without exposure to the drug

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Authors and Affiliations

  1. Investigational Drug Branch, National Cancer Institute, 20892, Bethesda, MD, USA

    Brenda J. Foster

  2. Medicine Branch, National Cancer Institute, 20892, Bethesda, MD, USA

    Karen R. Grotzinger, Wilma M. McKoy & Thomas C. Hamilton

  3. Biometric Research Branch, Division of Cancer Treatment, National Cancer Institute, 20892, Bethesda, MD, USA

    Lawrence V. Rubinstein

Authors
  1. Brenda J. Foster
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  2. Karen R. Grotzinger
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  3. Wilma M. McKoy
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  4. Lawrence V. Rubinstein
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  5. Thomas C. Hamilton
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Foster, B.J., Grotzinger, K.R., McKoy, W.M. et al. Modulation of induced resistance to adriamycin in two human breast cancer cell lines with tamoxifen or perhexiline maleate. Cancer Chemother. Pharmacol. 22, 147–152 (1988). https://doi.org/10.1007/BF00257313

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  • DOI: https://doi.org/10.1007/BF00257313

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