Shibutani, Suzuki, and Santosh

Tamoxifen is widely used as endocrine therapy for patients with breast cancer and recently was introduced as a prophylactic agent for healthy women at high risk of developing this disease. Unfortunately, long-term treatment of this drug increases significantly the risk of developing endometrial cancer. This serious adverse effect may reflect estrogenic activity or genotoxic properties of this drug. Recently, we found that tamoxifen- DNA adducts form in the endometrial tissue of certain women treated with this drug. We are exploring the metabolic activation and detoxification of tamoxifen and the mechanism of formation. mutagenicity and repair of tamoxifen-DNA adducts. To dissect these processes, we developed a highly sensitive and specific method for measuring tamoxifen-DNA adducts in animal and human tissues. Results of these molecular toxicological studies can be used to develop safer drugs for the chemoprevention of breast cancer.