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Inhibitory effects of the combination of HER-2 antisense oligonucleotide and chemotherapeutic agents used for the treatment of human breast cancer

Cancer Gene Therapy volume 8, pages 728–739 (2001)Cite this article

Abstract

Poor response to chemotherapy in patients with breast cancer is often associated with overexpression of HER-2/ neu. Interference with HER-2 mRNA translation by means of antisense oligonucleotides might improve the efficacy of chemotherapy. To test this hypothesis, eight breast cancer cell lines and a normal human fibroblast cell line were examined for their level of HER-2 expression, their sensitivity to phosphorothioate antisense oligonucleotides (AS HER-2 ODN), and to various chemotherapeutic agents, and the combination of the two. No correlation was found between the intrinsic HER-2 level and either the sensitivity to a particular chemotherapeutic agent alone, or the amount of growth inhibition observed with a specific AS HER-2 ODN concentration. Although sequence specificity and extent of AS HER-2 ODN inhibition of HER-2 synthesis were somewhat higher in the HER-2 overexpressing MDA-MB-453 and SK-BR-3 cells, we found that antisense treatment significantly sensitized all of the breast cancer cells, even MDA-MB-231 and MDA-MB-435 cells, with approximately basal levels of HER-2, to various chemotherapeutic agents. In addition, the combination of AS HER-2 ODN and taxol was shown to synergistically induce apoptosis in MDA-MB-435. These results demonstrate that overexpression of HER-2 would not be a prerequisite for the effective use of AS HER-2 ODN as a combination treatment modality for breast cancer and suggest that the use of AS HER-2 ODN, as part of a combination treatment modality, need not be limited to breast tumors that display elevated levels of HER-2. Cancer Gene Therapy (2001) 8, 728–739

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Acknowledgements

We thank Charles Kocher and Leanne Sleer for their assistance in the preparation of this manuscript, Dr. Karen Creswell for her help with the flow cytometry studies and the support of the Flow Cytometry/Cell Sorting and Tissue Culture Shared Resources of the Lombardi Cancer Center. This work was supported in part by National Foundation for Cancer Research Grant HU0001 (E.H.C.).

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Authors and Affiliations

  1. Departments of Oncology and Otolaryngology, Lombardi Cancer Center, Georgetown University Medical Center, 20007, Washington, DC, USA

    Antonina S Rait, Kathleen F Pirollo, Vladimir Rait, Laiman Xiang & Esther H Chang

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  1. Antonina S Rait
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  2. Kathleen F Pirollo
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  3. Vladimir Rait
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  4. Jeffrey E Krygier
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  6. Esther H Chang
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Correspondence to Esther H Chang.

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Rait, A., Pirollo, K., Rait, V. et al. Inhibitory effects of the combination of HER-2 antisense oligonucleotide and chemotherapeutic agents used for the treatment of human breast cancer. Cancer Gene Ther 8, 728–739 (2001). https://doi.org/10.1038/sj.cgt.7700359

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