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了高血压水平升高与 雌激素与乳腺癌的发展。尤其是天然荷尔蒙， 17B-雌二醇(E2)及其羟化代谢物，特别是， 4-羟基雌二醇(4-E2)是已知的动物致癌物质，已被 有牵连，并提出这些物质会导致游离 自由基介导的DNA损伤--参与乳腺发育的关键步骤 癌症。 我们在大鼠和人类组织中检测到了新的、极性的DNA加合物，包括 乳腺组织，通过新发展的32P-后标记/TLC分析。 与参比羟基化和环状加合物的色谱相似性 提示内源DNA加合物可能是氧自由基的结果 激进的调解。用药后大鼠的加合物水平升高 E2和4-E2，进一步支持自由基参与加合物 队形。DNA存在下Cu2+介导的4-雌二醇的活化 导致极性加合物的形成。一些在体外和体内形成的加合物 VIVE在层析上相似。总而言之，这些结果表明 极性加合物可能部分来自氧化还原循环或雌二醇组分。 代谢物。 我们假设雌激素E_2诱导的DNA加合物可能是 通过干预已知的或潜在的癌症化学预防而抑制 具有抗氧化潜力的药剂。我们的主要目标是找出有效的 抗氧化剂，以抑制E2介导的DNA氧化损伤。具体而言，1)至 确定已知的或潜在的化学预防药物对其疗效 体外抗氧化能力对抗DNA加合物诱导的氧化损伤 非酶的和酶的。2)确定所选药物的疗效 用E_2-大鼠乳腺癌模型抑制氧化DNA加合物的药物 模特。 本项目产生的数据将为制定详细的 与中间生物标记物(氧化DNA)相关的研究(RO1拨款) 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段。 随后可以计划对人体受试者进行研究。因此， 中间生物标记物方法可能最终确定哪些女性可能处于 发生乳腺癌的风险较高，在病理上尚未发病 可检测到的损伤。

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.