DEVELOPMENT OF BIOMARKERS FOR PREVENTION CLINICAL TRIALS

在美国，乳腺癌是女性的严重健康问题； 大约每九个人中就有一个会在她的手术期间患上乳腺癌 生活，尤其是绝经后的女性。有证据表明，乳房 减少饮食脂肪和增加摄入量可以降低患癌症的风险 水果和蔬菜。这两种饮食因素的功效是 目前正在进行两项全国性的临床试验，即 妇女健康倡议(WHI)和妇女干预营养 学习(胜利)。临床试验，使用癌症发病率或死亡率作为 终端，通常需要较长的持续时间、较大的受试者群体 和巨大的成本来实现统计意义；这些限制可能 如果合适的生物标记物反映中间终点，则绕过 可以辨认出来。我们提议的研究的目标是确定和 验证可准确、快速和 有效地监控干预剂的临床活动，并 确定高危对象。因为DNA碱基修饰是由 氧化和低甲基化被认为与 癌症的发展，我们的假设是，通过干预 减少膳食脂肪和增加水果和蔬菜的摄入量可以 减少DNA碱基修饰，从而降低患乳腺癌的风险。 DNA碱基修饰的三个可能的生物标志物，即8-羟基-2‘- 脱氧鸟苷、5-甲基-2‘-脱氧胞苷和丙二醛 易获得的人体标本--口腔粘膜细胞，外周白色 血细胞和尿液--将被评估。共有45例绝经后妇女 年龄在50岁至65岁之间、不同种族背景的妇女 将在3年内为拟议的试点研究招聘 试验分三个周期进行，每个周期15名受试者。每个周期都将 包括2个月的磨合期和6个月的饮食干预 句号。磨合结束后，受试者将被随机分配到 三组：对照组、低脂、低脂+高果蔬菜组。这个 干预将使脂肪摄入量从总卡路里的30%降至15%，并 将水果和蔬菜的摄入量从1-2份增加到5份 每天的服务。所获得的数据将用于确定：1) 基线值和个体内和个体间的变化 生物标志物；2)生物标志物水平与脂肪的关系 摄入量、血浆微量营养素、红细胞叶酸、血清雌激素和 血脂；3)生物标志物是否能够 由干预剂调节。当试点研究成功时 完成后，将请求新的赠款来执行扩展的 临床试验结合WHI和WINS来确定 介入剂对生物标志物的调节作用 与降低人类乳腺癌和其他癌症的风险有关。

In the US, breast cancer is a serious health problem for women; approximately one out of every nine will develop breast cancer during her life, especially postmenopausal women. Evidence has indicated that breast cancer risk may be decreased by dietary fat reduction and increased intake of fruits & vegetables. The efficacies of these two dietary factors are currently being investigated in two nationwide clinical trials, i.e. the Women's Health Initiative (WHI) and the Women's Intervention Nutrition Study (WINS). Clinical trials, using cancer incidence or mortality as endpoints, usually require a lengthy duration, large subject populations and huge costs to achieve statistical significance; these limitations can be circumvented if suitable biomarkers reflecting intermediate endpoints can be identified. The goal of our proposed research is to identify and validate putative biomarkers that can be used accurately, quickly, and efficiently to monitor the clinical activity of intervention agents and to identify high risk subjects. Since DNA base-modifications as a result of oxidation and hypomethylation have been suggested to be associated with the development of cancers, our hypothesis is that intervention with dietary fat reduction and increased intake of fruits & vegetables can decrease the DNA base-modifications, and hence reduce breast cancer risk. Three putative biomarkers of DNA base-modifications, namely 8-hydroxy-2'- deoxyguanosine, 5-methyl-2'-deoxycytidine and malondialdehyde, in three easily accessible human specimens--buccal mucosal cells, peripheral white blood cells and urine--will be evaluated. A total of 45 postmenopausal women between the ages of 50 to 65 years and of all ethnic backgrounds will be recruited in 3 years for the proposed pilot study which will be carried out in three cycles, 15 subjects per cycle. Each cycle will consist of a 2-month run-in period and a 6-month dietary intervention period. After the run-in, the subjects will be randomly assigned into three groups: control, low-fat, and low fat+high-fruits & vegetables. The intervention will reduce fat intake from >30% to 15% of total calories and increase the intake of fruits and vegetables from 1-2 servings to > 5 servings per day. The data obtained will be used to determine: 1) the baseline values and the intra- and inter-individual variation of the biomarkers; 2) the relationship between the levels of biomarkers and fat intake, plasma micronutrients, red blood cell folate, serum estrogen and serum lipids; and 3) whether or not the biomarkers are able to be modulated by the intervention agents. When the pilot study is successfully accomplished, a new grant will be requested to carry out an expanded clinical trial in conjunction with the WHI and the WINS to determine whether or not the modulation of the biomarkers by the intervention agents is associated with a reduced risk of human breast and other cancers.