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mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy: correlation with expression of bcl-2 family members

Cancer Gene Therapy volume 13, pages 490–502 (2006)Cite this article

Abstract

Current therapies used in the treatment of breast cancer are limited by systemic toxicity, rapid drug metabolism and intrinsic and acquired drug resistance. We have previously shown that adenoviral-mediated transfer of the melanoma differentiation-associated gene-7 (mda-7) elicits growth inhibition and apoptosis in various tumor types. Here, we evaluate the effects of Ad-mda7, alone and in combination with other therapies, against a panel of nine breast tumor cell lines and their normal counterparts; we report selective Ad-mda7-mediated p53-independent growth inhibition, G2/M cell cycle arrest, and apoptosis. In vivo, Ad-mda7 induced p53-independent tumor growth inhibition (P<0.004) in multiple xenograft models. We then evaluated the combination of Ad-mda7 with agents commonly used to treat breast cancer: radiotherapy (XRT), Tamoxifen, Taxotere, Adriamycin, and Herceptin. These agents exhibit diverse modes of action, including formation of bulky adducts, inhibition of DNA replication (Adriamycin, XRT), damage to microtubules (Taxotere), nonsteroidal estrogen antagonists (Tamoxifen), or Her2/neu receptor blockade (Herceptin). Treated with conventional anticancer drugs or radiation, MDA-7-expressing cells display additive or synergistic cytotoxicity and apoptosis that correlates with decreased BCL-2 expression and BAX upregulation. In vivo, animals that received Ad-mda7 and XRT underwent significant reduction of tumor growth (P<0.002). This is the first report of the synergistic effects of Ad-mda7 combined with chemotherapy or radiotherapy on human breast carcinoma cells.

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Acknowledgements

This work was supported by NCI Grants CA89778, CA88421, CA102716 (RR) and CA097598 (SC); PO1 CA06294 (REM) the Texas Higher Education Coordinating Board ATP/ARP Grant 003657-0078-2001 (RR), by Institutional Research Grant (RR), and by WM Keck Gene Therapy Grant (RR); The University of Texas MD Anderson Cancer Center Support Core Grant (CA 16672) (KKH); The Shooting Down Cancer Fund (MD Anderson Cancer Center: KKH); The Cheryl Burguieres Memorial Breast Cancer Fund (MD Anderson Cancer Center: KKH), and a sponsored research agreement with Introgen Therapeutics, Inc., The Homer Flower Gene Therapy Research Fund (SGS).

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Authors and Affiliations

  1. Introgen Therapeutics Inc., Houston, TX, USA

    S Chada, A M Mhashilkar & M Zheng

  2. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Liu, S A Vorburger, K Kawase & K K Hunt

  3. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T Nishikawa & R E Meyn

  4. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Bocangel, A Pataer, S G Swisher & R Ramesh

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Correspondence to S Chada.

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Chada, S., Mhashilkar, A., Liu, Y. et al. mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy: correlation with expression of bcl-2 family members. Cancer Gene Ther 13, 490–502 (2006). https://doi.org/10.1038/sj.cgt.7700915

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