Effects of Low Dose CT Radiation on Lung Tumorigenesis

描述(由申请人提供)： 在美国，肺癌是癌症相关死亡的主要原因，总体5年存活率为15%。在没有其他症状的患者中发现早期病变的能力将增加生存的可能性。最近，人们研究了每年一次的低剂量CT，以确定其在筛查无症状的癌症高危人群(即有显著吸烟史)方面的价值。然而，每年一次的CT肺部筛查的效果和效果在很大程度上是未知的。CT筛查过程可能存在风险，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上相关的CT筛查程序对导致辐射诱发癌变的可能性的影响。我们将利用代表肺肿瘤发生最早阶段的转基因小鼠模型，并采用标准的完全致癌和肺肿瘤形成的启动/促进方案，利用在香烟烟雾中普遍存在并与肺肿瘤发病机制有关的几类化学致癌物。我们还将确定在常规全身或肺CT筛查中接受的辐射剂量是否会增加氧化应激的生物标记物(pNF-kb、COX-2、iNOS或羰基蛋白氧化)，这些生物标记物可能与肺癌形成和/或促进/进展的任何影响(或缺乏)有机械上的联系。由此产生的数据将对临床使用CT确定临床低剂量CT暴露导致癌症发展的风险产生重大影响。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，人们研究了每年一次的低剂量CT，以确定其在筛查无症状的肺癌高危人群中的价值，然而，每年一次的CT肺部筛查的效果在很大程度上是未知的。这项拟议中的研究将确定，CT这项可以降低美国癌症死亡率最大单一原因的技术，是否可以被证明是一种筛查工具，用于检测无症状吸烟者和戒烟者的肺部病变，因为其好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.