Oxidative Damage and DNA Repair in the PCPT

描述（由申请人提供）：前列腺癌预防试验（PCPT）的finaldade 导致干预组中癌症的减少;然而，在诊断为前列腺癌的男性中，finaldehydde组中具有高Gleason评分的肿瘤的绝对数量大于安慰剂组。许多已知和疑似前列腺癌的风险因素与较高水平的活性氧（ROS）或抗氧化能力降低有关。氧化应激是由ROS和抗氧化能力之间的不平衡引起的，这可能导致直接的DNA损伤和突变。存在广泛的DNA修复系统，其可以在细胞复制和突变固定之前校正受损的DNA，尽管固有的变异性可以导致DNA修复能力降低。在这个修订后的应用程序中提出的关于前列腺癌中DNA修复和氧化应激的额外数据进一步加强了这两种途径参与风险的假设。使用在PCPT和本P01的其他项目中收集的生物标本和数据，我们打算：1）评估与氧化应激/DNA修复机制相关的前列腺癌的潜在风险因素; 2）研究芬普胺与高级别肿瘤相关的机制。我们将确定编码产生ROS、中和ROS和修复DNA损伤的酶的基因多态性是否与前列腺癌和高级别癌症的风险相关。我们还将测量氧化蛋白（氧化损伤的生物标志物）的血清水平，以确定那些继续发展癌症的人的氧化应激基线水平是否升高，以及芬迪是否影响其水平。在跨项目的互动目标中，我们将与P01中其他项目的研究人员合作，以更好地了解氧化应激和DNA修复在前列腺癌风险中的作用。在项目2中，我们将确定饮食因素与前列腺癌的关联是否因氧化应激基因型而异，在项目4中，氧化应激和DNA修复基因的基因型是否与萎缩和炎症的患病率和程度相关。

DESCRIPTION (provided by applicant): The Prostate Cancer Prevention Trial (PCPT) of finasteride resulted in reduced cancers among the intervention group; however, among the men diagnosed with prostate cancer, the absolute number of tumors with high Gleason score was greater in the finasteride arm than in the placebo arm. Many of the known and suspected risk factors for prostate cancer are associated with higher levels of reactive oxygen species (ROS) or decreased antioxidant capabilities. Oxidative stress results from an imbalance between ROS and antioxidant capacities, which can cause direct DNA damage and mutations. There are extensive DNA repair systems that can correct damaged DNA before cell replication and mutation fixation, although inherent variability can result in diminished DNA repair capabilities. Additional data presented in this revised application on DNA repair and oxidative stress in prostate cancer further strengthen the hypothesis that these two pathways are involved in risk. Using biospecimens and data collected in PCPT and in the other projects of this P01, we intend to: 1) evaluate potential risk factors for prostate cancer that are linked to an oxidative stress/DNA repair mechanism; and 2) investigate mechanisms whereby finasteride could be associated with high grade tumors. We will determine whether polymorphisms in genes encoding enzymes that generate ROS, neutralize ROS, and repair DNA damage are associated with risk of prostate cancer and high grade cancer. We will also measure serum levels of oxidized proteins, a biomarker of oxidative damage, to determine if baseline levels of oxidative stress are elevated in those who go on to develop cancer and whether finasteride influences its level. In cross-project interactive aims, we will collaborate with investigators in other projects in this P01 to better understand the role of oxidative stress and DNA repair in prostate cancer risk. With Project 2, we will determine whether associations of dietary factors with prostate cancer differ by oxidative stress genotype and with Project 4 whether genotype for oxidative stress and DNA repair genes are associated with prevalence and extent of atrophy and inflammation.