Weight Loss & Cancer Biomarkers in Women: 0xidative Stress & Inflammation

描述(申请人提供)：超重、肥胖和久坐不动的生活方式与女性患多种癌症的风险增加有关，包括结肠癌、子宫内膜癌、绝经后乳腺癌、肾癌和下段食道癌。有证据表明，肥胖和久坐不动的生活方式造成的一些糖尿病和心血管不良后果也与几种癌症的病因有关。在实验室和流行病学研究中，氧化应激、炎症和二十烷类化合物参与了肿瘤发生和发展的几个阶段，与癌症的风险或进展有关。它们也与超重/肥胖或久坐不动的生活方式有关。然而，超重/肥胖女性的减肥或锻炼对这些生物标志物的影响尚未确定。代谢综合征是各种慢性病的一组风险因素，与肥胖有关，它或其组成部分与癌症风险增加有关。我们建议调查一项完整的为期12个月的随机对照临床试验的效果，该试验测试了3种导致体重减轻和/或增加体力活动的干预措施：1)减少卡路里饮食体重减少(平均9%体重减轻，N=118)；2)中等强度有氧运动(225分钟/周，平均3%体重减轻，N=117)；3)两种干预措施(平均11%体重减轻，N=116)；与4)对照组(无体重变化，N=87)。拟议研究的主要目的是与对照组相比，测试干预措施对以下方面的影响：1)氧化应激(血浆F2-异前列腺素、荧光氧化产物、氧化低密度脂蛋白)；2)血浆炎症标记物(TNF1、TNF1-受体2)和抗炎标记物IL-10；以及3)代谢综合征的患病率。第二个具体目标是检查其他因素在多大程度上改变饮食减肥或锻炼与拟议生物标志物之间的关系：a)超重/肥胖和基线时的身体脂肪质量；以及b)身体成分(体重，身体脂肪百分比)在干预过程中的变化。一个探索性的目的是在206名女性中测试对尿液前列腺素PGE2代谢物(PGE-M)和白三烯LTE4的干预效果。这项新颖的研究结果将阐明女性能量平衡与癌症之间的潜在机制，这将有助于开发降低几种癌症风险的干预措施。

DESCRIPTION (provided by applicant): Overweight, obesity, and sedentary lifestyles are associated with an increased risk for several cancers in women, including colon, endometrium, postmenopausal breast, kidney, and lower esophageal cancer. Evidence suggests that some of the diabetogenic and adverse cardiovascular consequences of obesity and a sedentary lifestyle are also involved in the etiology of several cancers. Oxidative stress, inflammation, and eicosanoids, which are involved in several phases of carcinogenesis and tumor progression, have been associated with risk or progression of cancers in laboratory and epidemiologic studies. They have also been associated with overweight/obesity or a sedentary lifestyle. The effects of weight loss or exercise in overweight/obese women on these biomarkers are not established, however. The Metabolic Syndrome, a set of risk factors for various chronic diseases, is related to obesity, and it, or its components, are associated with increased cancer risk. We propose to investigate the effects of a completed 12-month randomized controlled clinical trial that tested 3 interventions leading to weight loss and/or increased physical activity: 1) reduced calorie dietary weight loss (mean 9% weight loss, N=118); 2) moderate intensity aerobic exercise (225 min/wk, mean 3% weight loss, N=117); 3) both interventions (mean 11% weight loss, N=116); vs. 4) control (no weight change, N=87) in postmenopausal overweight/obese women aged 50-75 years. The primary aims of the proposed study are to test, compared to controls, the effects of interventions on: 1) oxidative stress (plasma F2-isoprostane, fluorescent oxidation products, oxidized LDL); 2) plasma inflammation markers (TNF1, TNF1- receptor 2) and the anti-inflammation marker IL-10; and 3) prevalence of the Metabolic Syndrome. The secondary specific aims are to examine the extent to which other factors modify the associations between dietary weight loss or exercise with the proposed biomarkers: a) overweight/obesity and body fat mass at baseline; and b) body composition (weight, % body fat) changes during the course of the interventions. An exploratory aim will test intervention effects in a subset of 206 women, on urine prostaglandin PGE2 metabolite (PGE-M) and leukotriene LTE4. The results of this novel study will elucidate potential mechanisms linking energy balance to cancer in women, which will aid in the development of interventions for reducing risk for several cancers.