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Targeting Oncogenes to Improve Breast Cancer Chemotherapy

¹ Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas and ² Lexicon Genetics, Inc., The Woodlands, Texas

Requests for reprints: Karen M. Vasquez, Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, 1808 Park Road 1-C, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9324; Fax: 512-237-2475; E-mail: kvasquez{at}mdanderson.org.

Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by 40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site 4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors. (Cancer Res 2006; 66(8): 4089-94)

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