Oxidative Damage and DNA Repair in the PCPT

描述(申请人提供)：非那雄胺的前列腺癌预防试验(PCPT) 结果，在干预组中，癌症减少；然而，在被诊断为前列腺癌的男性中，服用非那雄胺组的肿瘤绝对数高于服用安慰剂组的患者。许多已知和怀疑的前列腺癌危险因素与活性氧簇(ROS)水平较高或抗氧化能力降低有关。氧化应激是由于ROS和抗氧化能力之间的失衡造成的，这可能导致直接的DNA损伤和突变。有广泛的DNA修复系统可以在细胞复制和突变固定之前纠正受损的DNA，尽管固有的变异性会导致DNA修复能力减弱。在这项关于前列腺癌DNA修复和氧化应激的修订申请中提出的其他数据进一步加强了这两条途径与风险有关的假设。利用在PCPT和P01其他项目中收集的生物样品和数据，我们打算：1)评估与氧化应激/DNA修复机制有关的前列腺癌的潜在风险因素；2)研究非那雄胺可能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有关。我们还将测量血清氧化蛋白水平，这是氧化损伤的生物标志物，以确定在那些继续发展为癌症的人中，氧化应激的基线水平是否升高，以及非那雄胺是否影响其水平。在跨项目互动目标中，我们将在P01的其他项目中与研究人员合作，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相关性是否因氧化应激基因型而不同，并将与项目4确定氧化应激和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.