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Acquired Tamoxifen Resistance and Overexpression of Anti-Apoptotic Molecules: A Potential Strategy for Overcoming Endocrine Resistance
Final rept. 21 Jun 2003-20 Jan 2005
MICHIGAN UNIV ANN ARBOR
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The major goal of this Concept Award project is to investigate whether a small molecule inhibitor of Bcl-xL will be able to overcome the chemo- and endocrine-resistance in breast cancer. we have investigated the in vitro and anti-tumor activity of --gossypol, a potent small molecule inhibitor of Bcl-xL, and the potential synergistic effects of --gossypol in combination with chemodrugs and Tamoxifen in breast cancer cell lines. --gossypol showed potent anti-tumor activity to human breast cancer cell lines with high levels of Bcl-xL, but has only minimal effect on human normal breast epithelial cells with low Bcl-xL. --gossypol potently enhanced growth inhibition by doxorubicin and docetaxel, currently used chemotherapeutic agents for breast cancer, both in vitro and in vivo. However, --gossypol did not show significant enhancement of Tamoxifen activity in Er breast cancer MCF-7 and T47D cells. Bcl-xL knockdown by siRNA abolished the tumorigenecity of MCF-7 cells. The data support that Bcl-xL plays a critical role in breast cancer initiation, progression and chemoresistance, but its role in endocrine resistance remains to be further elucidated. The study provide us a solid foundation to develop --gossypol as a novel molecular targeted therapy for the treatment of breast cancer with Bcl-xL overexpression.
APPROVED FOR PUBLIC RELEASE