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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Authors | S Chada, A M Mhashilkar, Y Liu, T Nishikawa, D Bocangel, M Zheng, S A Vorburger, A Pataer, S G Swisher, R Ramesh, K Kawase, R E Meyn, K K Hunt |
Journal | Cancer gene therapy
(Cancer Gene Ther)
Vol. 13
Issue 5
Pg. 490-502
(May 2006)
ISSN: 0929-1903 [Print] England |
PMID | 16282987
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interleukins
- Proto-Oncogene Proteins c-bcl-2
- interleukin-24
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Topics |
- Adenoviridae
(genetics)
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Apoptosis
- Biological Therapy
- Breast Neoplasms
(drug therapy, radiotherapy, therapy)
- Carcinoma
(drug therapy, radiotherapy, therapy)
- Combined Modality Therapy
- Female
- Gene Transfer Techniques
- Genetic Therapy
- Humans
- Interleukins
(genetics)
- Mice
- Mice, Inbred BALB C
- Proto-Oncogene Proteins c-bcl-2
(analysis, metabolism)
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