Tamoxifen, an antiestrogen used in the endocrine therapy and chemoprevention of breast cancer, induces liver cancer in rodents and is associated with endometrial cancer in women. Estrogens also are implicated in the etiology of endometrial and breast cancer. The carcinogenicity of these agents may be mediated through their genotoxic effects. The goals of this research are to establish a mechanism for the genotoxicities of tamoxifen and estrogen and to find a safer alternative to tamoxifen. Oligodeoxynucleotides containing a single defined DNA adduct will be prepared by automated DNA synthesis. Using these site-specifically modified oligodeoxynucleotides, the mutagenic and repair potential of estrogen and anti-estrogen DNA adducts in mammalian cells will be determined. The three dimensional structure of tamoxifen- and estrogen adducts in DNA duplex also will be established, permitting us to understand the process of mutagenic and repair events which occur at lesion sites. Such modified oligodeoxynucleotides also will be employed as standards in ultrasensitive 32P-postlabeling and HPLC/electrochemical detector analyses designed to quantify DNA adducts and oxidatively damaged lesions in the tissues of rodents and monkeys treated with these drugs. Taken together, this information can be used to predict genotoxicity. Translational studies have been designed to detect adducts in the endometrial DNA of patients undergoing treatment with tamoxifen or toremifene. These experiments will provide biomarkers for molecular epidemiological studies and explore the relationship between tamoxifen therapy and the development of endometrial cancer in women treated with this drug. This research should lead to a safer alternative for women undergoing breast cancer therapy and for chemoprevention.
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