Effects of Low Dose CT Radiation on Lung Tumorigenesis

描述（由申请人提供）： 肺癌是美国癌症相关死亡的主要原因，总的5年生存率为15%。在其他无症状的患者中检测早期病变的能力将增加生存的可能性。最近，已经研究了年度低剂量CT以确定其用于筛查处于癌症高风险的无症状个体（即，有严重吸烟史）。然而，每年CT肺部筛查的有效性和效果在很大程度上是未知的。可能存在与CT筛查过程相关的风险，因为使用电离辐射可能会导致肿瘤的发展。因此，我们建议使用三种不同的小鼠肺癌模型来确定临床相关的CT筛查程序对引起辐射诱导的致癌作用的可能性的影响。我们将利用一个转基因小鼠模型的肺肿瘤发生的最早阶段的代表，并采用一个标准的完整的致癌作用和启动/促进协议的肺肿瘤的形成，利用类化学致癌物，是普遍存在于香烟烟雾和牵连在肺肿瘤的发病机制。我们还将确定在常规全身或肺CT筛查期间接受的辐射剂量是否增加氧化应激的生物标志物（pNF-kb、考克斯-2、iNOS或羰基蛋白氧化），其可能与对肺肿瘤形成和/或促进/进展的任何影响（或缺乏影响）机械相关。由此产生的数据将对CT的临床使用产生重大影响，以确定临床低剂量CT暴露的癌症发展风险。公共卫生相关性：肺癌是美国癌症相关死亡的主要原因，最近研究了年度低剂量CT，以确定其筛查肺癌高风险无症状个体的价值，然而，年度CT肺部筛查的效果在很大程度上是未知的。拟议的研究将确定CT技术是否可以作为一种筛查工具来检测无症状吸烟者和戒烟者的肺部病变，因为其益处超过了辐射诱发肺癌的风险。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in the U.S., with an overall 5 year survival rate of pound15%. The ability to detect early stage lesions in otherwise asymptomatic patients would increase the likelihood of survival. Recently, annual low-dose CT has been studied to determine its value for screening asymptomatic individuals that are at high risk for cancer (i.e., significant smoking history). However, the efficacy and effects of annual CT lung screening are largely unknown. There may be a risk associated with the CT screening process, as the use of ionizing radiation could potentially cause the development of tumors. We thus propose to determine the effect of clinically relevant CT screening procedures on the potential to cause radiation-induced carcinogenesis using three different mouse models of lung carcinogenesis. We will utilize a transgenic mouse model representative of the earliest stages of lung tumorigenesis and employ both a standard complete carcinogenesis and an initiation/promotion protocol of lung tumor formation, utilizing classes of chemical carcinogens that are prevalent in cigarette smoke and are implicated in lung tumor pathogenesis. We will also determine if the radiation doses received during routine whole-body or lung CT screening increase biomarkers of oxidative stress (pNF-kb, COX-2, iNOS, or carbonyl protein oxidation) that can be mechanistically related to any effects (or lack thereof) on lung tumor formation and/or promotion/progression. The resulting data will have a significant impact on the clinical use of CT in determining the risk of cancer development from clinical low-dose CT exposure. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer-related deaths in the U.S. Annual low-dose CT has been recently studied to determine its value for screening asymptomatic individuals that are at high risk for lung cancer, however, the effects of annual CT lung screening are largely unknown. The proposed studies will determine if CT, a technique that could reduce the single biggest cause of cancer mortality in the US, can be justified as a screening tool to detect lung lesions in asymptomatic smokers and ex- smokers because the benefits outweigh the risk of radiation-induced lung cancer.