Role of Antioxidants in Breast Cancer Prevention

描述（由申请人提供）： 流行病学研究已经确定， 雌激素与乳腺癌的发展。尤其是天然激素， 17 b-雌二醇（E2）及其羟基化代谢物，特别是， 4-羟乙烯（4-E2）是已知的动物致癌物， 它暗示，并提出，这些物质造成免费的 自由基介导的DNA损伤是乳腺发育的关键步骤， 癌 我们已经在大鼠和人体组织中检测到新型极性DNA加合物，包括 乳腺组织，通过新开发的32 p-后标记/TLC测定。 与参比羟基化和环状加合物的色谱图相似性 表明内源性DNA加合物可能是由无氧 激进调解大鼠中的加合物水平在用 E2和4-E2，进一步支持自由基参与加合物 阵在DNA存在下，Cu 2+介导的4-E2活化也 导致极性加合物形成。一些加合物在体外和体内形成， 体内色谱相似。综合这些结果， 极性加合物可能部分来自氧化还原循环或E2 代谢物。 我们假设，雌激素E2诱导的氧化DNA加合物可能是 通过已知或潜在的癌症化学预防剂干预抑制 抗氧化剂的潜力。我们的主要目标是确定有效的 抗氧化剂抑制E2介导的氧化DNA损伤。具体而言，1） 确定已知或潜在的化学预防剂的功效， 体外抗氧化潜力对氧化DNA加合物诱导 非酶促和酶促。2)为了确定选定的 使用E2-大鼠乳腺癌发生抑制氧化DNA加合物的试剂 模型 从这个项目产生的数据将制定详细的基础 研究（RO 1赠款），以关联中间生物标志物（氧化DNA 损伤、DNA修复活性、细胞凋亡、基因突变和细胞增殖） 疾病终点在大鼠乳腺肿瘤发生的不同时间间隔。 随后可以计划使用人类受试者进行研究。因此 中间生物标志物方法可以最终确定可能处于 在病理学上发病之前，患乳腺癌的风险较高 可检测的损伤

DESCRIPTION (provided by applicant): Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular, the natural hormone, 17b-estradiol (E2) and its hydroxylated metabolites, particularly, 4-hydroxyestradiol (4-E2), which are known animal carcinogens, have been implicated and it is proposed that these substances cause free radical-mediated DNA damage, a key step involved in the development of breast cancer. We have detected novel, polar DNA adducts in rat and human tissues, including mammary tissue, by a newly developed 32p-postlabeling/TLC assay. Chromatographic similarity with reference hydroxylated and cyclic adducts suggested that the endogenous DNA adducts presumably resulted from oxygen free radical-mediation. Adduct levels in rats were increased after treatment with E2 and 4-E2, further supporting the involvement of free radicals in the adduct formation. Cu2+-mediated activation of 4-E2 in the presence of DNA also resulted in polar adduct formation. Some of the adducts formed in vitro and in vivo were chromatographically similar. Taken together these results suggest that the polar adducts may result, in part, from redox cycling or E2 metabolites. We hypothesize that oxidative DNA adducts induced by the estrogen, E2 can be inhibited by intervention with known or potential cancer chemopreventive agents of antioxidant potential. Our main objective is to identify effective antioxidants to inhibit E2-mediated oxidative DNA damage. Specifically, 1) To determine the efficacy of known or potential chemopreventive agents for their antioxidant potential in vitro against oxidative DNA adducts induced non-enzymatically and enzymatically. 2) To determine the efficacy of selected agents to inhibit oxidative DNA adducts using E2-rat mammary carcinogenesis model. Data resulting from this project will formulate the basis of detailed investigations (RO1 grant) to correlate intermediate biomarkers (oxidative DNA damage, DNA repair activity, apoptosis, gene mutations and cell proliferation) with the disease endpoint at different intervals of rat mammary tumorigenesis. Studies can subsequently be planned with human subjects. Thus, the intermediate biomarker approach may ultimately identify women who may be at higher risk of developing breast cancer, before the onset of pathologically detectable lesions.