Tamoxifen (TMX) is an antiestrogenic compound used in the treatment of breast and other cancers. Women treated with TMX have been reported to show up to a 6-fold increased risk for the development of uterine cancer. Studies from the applicant's laboratory suggest that TMX usage may result in the formation of DNA damage in human endometrium. In these studies the applicant proposes to: (1) collect endometrial biopsy samples from a group of women with varying TMX usage. Patient medical records will be used to asses TMX usage and a questionnaire will be used to analyze other variables includin age, menopausal status, and tobacco history. (2) Measure levels of TMX metabolites and uterine peroxidase activity in the endometrial samples. These measurements will be treated as biomarkers of internal TMX dose and individual capacity to activate TMX metabolites to form DNA damage. (3) Measure levels of DNA adducts and 8-hydroxydeoxy-7,8- dihydroguanosine in the endometrial samples Attempts will be made to verify that the adducts detected in the endometrial samples are derived from TMX by direct analysis with liquid chromatography-mas spectrometry. (4) Identify the structure of the DNA adduct formed by 4-OH-TMX. (5) Develop a model to test for associations between TMX usage and the formation of DNA adducts and 8-hydroxydeoxy-7,8-dihydroguanosine in endometria samples. The applicant will seek to determine if any association is modified by either levels of TMX metabolites in endometrial samples, activity of uterine peroxidase, or tobacco smoking history. Statistical power has been considered regarding the hypothesis that administration of TMX results in the formation of DNA damage in human endometrium.
