The Selective Estrogen Receptor Modulator (SERM), tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer, and recently completed large-scale clinical trials have validated tamoxifen as a breast cancer chemopreventive agent. Several studies have raised concern over the safety of chronic treatment with SERMs, in particular with respect to induction of endometrial cancer. Alternative SERMs including raloxifene, may not be genotoxic possibly because of different routes of metabolism which could lead to a decrease in amount and/or type of ultimate carcinogen(s). Raloxifene is being compared to tamoxifen in a large chemoprevention trial, is in clinical use in osteoporosis and in clinical trials to examine efficacy in prevention of cardiovascular disease. The cardiovascular activity of SERMs is mediated through elevation of cellular nitric oxide (NO). The central hypothesis of this proposal is that the demonstrated elevation of tissue NO levels by SERMs in various tissues is intrinsically linked with their cytoprotective, cytotoxic and carcinogenic properties. SERM-induced elevation of NO in tissue under oxidative stress will generate RNOS and peroxynitrite, a known tumor promoter. RNOS and peroxynitrite are capable of oxidation and nitration of various biomolecules, and of SERMs themselves. SERM metabolites have the capacity to covalently modify biomolecules, including DNA and the estrogen receptor (ER), in addition to generating superoxide, contributing to oxidative stress through depletion of cellular reducing equivalents, and leading to protein S-nitrosylation.
Specific aims : 1. Assess cytotoxic pathways for SERM/NO interactions in subcellular systems. 2. Assess the cytotoxicity of products from the reactions of NO and peroxynitrite with SERMs and their metabolites in cell lines and assess antagonist/agonist activity of SERMS and their metabolites in cell lines and with purified estrogen receptor. 3. Assess the cytotoxicity and activity of products from SERM/NO interactions in vascular and uterine tissue. The completion of these specific aims will define potential for cyto/genotoxic interactions between SERMs and NO and cellular targets. ? ?
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