DEVELOPMENT OF BIOMARKERS FOR PREVENTION CLINICAL TRIALS

在美国，乳腺癌是妇女的一个严重健康问题; 大约每九个人中就有一个人会在她怀孕期间患上乳腺癌。 尤其是绝经后的女性。有证据表明，乳房 减少饮食中的脂肪和增加摄入量可以降低癌症风险 水果和蔬菜。这两种饮食因素的功效是 目前正在两项全国性临床试验中进行研究，即 妇女健康倡议（WHI）和妇女干预营养 研究（A）。临床试验，使用癌症发病率或死亡率作为 终点，通常需要较长的持续时间，大量受试者人群 以及实现统计显著性的巨大成本;这些限制可以 如果合适的生物标志物反映了中间终点， 可以被识别。我们研究的目的是确定和 验证可以准确、快速使用的假定生物标志物， 有效地监测干预剂的临床活性， 识别高风险对象。由于DNA碱基的改变， 氧化和低甲基化被认为与 癌症的发展，我们的假设是， 减少饮食脂肪和增加水果和蔬菜的摄入量， 减少DNA碱基修饰，从而降低乳腺癌风险。 三种推定的DNA碱基修饰的生物标志物，即8-羟基-2 '- 脱氧鸟苷、5-甲基-2 '-脱氧胞苷和丙二醛， 易于获取的人类标本-颊粘膜细胞，外周白色 血细胞和尿液会被检测共有45名绝经后妇女 年龄在50至65岁之间的所有种族背景的妇女 将在3年内招募进行拟议的试点研究， 分三个周期进行，每个周期15名受试者。每个循环将 包括2个月的导入期和6个月的饮食干预 期导入后，受试者将被随机分配到 三组：对照组、低脂组和低脂+高果蔬组。的 干预将使脂肪摄入量从总热量的>30%减少到15%， 将水果和蔬菜的摄入量从1-2份增加到> 5份 每天的服务量。获得的数据将用于确定：1） 基线值和个体内和个体间变异 生物标志物; 2）生物标志物水平与脂肪之间的关系 摄入量，血浆微量营养素，红细胞叶酸，血清雌激素和 血清脂质;以及3）生物标志物是否能够被 由干预剂调节。试点研究成功后， 完成后，将要求一笔新的赠款， 临床试验结合WHI和WHI，以确定 无论干预剂对生物标志物的调节 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.