Mitigation of Radiation Pneumonitis and Fibrosis

描述(由申请人提供)： 该项目将测试血管紧张素转换酶抑制剂依那普利对接受肺癌放射治疗的退伍军人的放射性肺炎和纤维化的缓解效果。它是基于人类正常组织辐射损伤可以安全有效地减轻的假设，以及我们在实验动物中进行的广泛的放射缓解研究。肺癌在退伍军人中比在普通人群中更常见；该项目与退伍军人的医疗保健高度相关。具体目标是：1.检验 依那普利是一种血管紧张素转换酶抑制剂，用于减轻人体放射性肺炎和纤维化。A.依那普利或安慰剂将在#年开始照射后立即开始使用 对接受放射治疗的肺癌患者，以及他们对放射性肺炎和纤维化的影响进行比较。将使用依那普利而不是卡托普利，因为依那普利每天只服用一次剂量。2.探讨依那普利减轻放射性肺损伤的作用机制。A.血管紧张素原、血浆肾素活性和血管紧张素II 将在所有受试者中作为肾素-血管紧张素系统标记物进行测量。将评估依那普利对每个标志物的影响，并与安慰剂进行比较。3.确认此用途的依那普利不会对癌症治疗结果产生不利影响。A.对依那普利组和安慰剂组的癌症复发和癌症死亡率进行比较。这些研究将在接受肺癌放射治疗的男性和女性身上进行。依那普利，或外观相同的安慰剂，将在放射治疗开始时开始使用。依那普利或安慰剂的疗效将通过它们对2级或更严重的临床放射性肺炎的影响，通过它们对肾素-血管紧张素系统标记物血管紧张素原、血浆肾素活性、血管紧张素II的影响以及它们对肺炎和纤维化的放射学证据的影响来测试。我们工作的广泛和长期目标是实现对任何组织类型的正常组织辐射损伤的有效和安全的缓解。我们和其他人利用实验室大鼠模型，成功地减轻了肾、肺、皮肤和脑的正常组织辐射损伤(NTRI)。这些人体研究的成功将对肺部有NTRI风险的受试者产生很大影响。这将改善患有肺癌的退伍军人的健康，这与退伍军人事务部的使命高度相关。这一成功将是将放射缓解概念扩展到放射治疗期间其他有风险的正常组织，如脊髓或脑的重要推动力。

DESCRIPTION (provided by applicant): This project will test the effect of enalapril, an angiotensin-converting-enzyme inhibitor, to mitigate radiation pneumonitis and fibrosis in veterans undergoing radiation therapy for lung cancer. It is based on the hypothesis that human normal tissue radiation injury can be safely and effectively mitigated, and on our extensive studies of radiomitigation in experimental animals. Lung cancer is more common in veterans than in the general population; this project is highly relevant to the medical care of veterans. The specific aims are: 1. To test the benefit of enalapril, an angiotensin-converting-enzyme-inhibitor, to mitigate radiation pneumonitis and fibrosis in humans. a. Enalapril or placebo will commence right after the start of irradiation in patients undergoing radiation therapy for lung cancer, and their effects on radiation pneumonitis and fibrosis will be compared. Enalapril will be used rather than captopril, because enalapril is given in single daily doses. 2. To test the mechanism of mitigation of radiation lung injury by enalapril. a. Angiotensinogen, plasma renin activity, and angiotensin II will be measured as renin-angiotensin system markers in all subjects. b. The effect of enalapril on each marker will be assessed, as compared to placebo. 3. To confirm that enalapril in this use does not adversely affect cancer treatment outcomes. a. Cancer recurrence and death from cancer will be compared for the enalapril and placebo groups. These studies will be done in men and women undergoing radiation therapy for lung cancer. Enalapril, or identical-appearing placebo, will be started at the beginning of the radiation treatments. The effect of the enalapril or placebo will be tested by their effect on grade 2 or greater clinical radiation pneumonitis, by their effect on the renin-angiotensin system markers angiotensinogen, plasma renin activity, angiotensin II, and their effect on radiographic evidence of pneumonitis and fibrosis. The broad, long-term objective of our work is to achieve effective and safe mitigation o normal tissue radiation injuries for any tissue type. We and others have successfully mitigated normal tissue radiation injury (NTRI) of kidneys, lungs, skin, and brain, using laboratory rat models. The success of these human studies will have a high impact for subjects at risk of NTRI to the lungs. This will improve the health of veterans with lung cancer, which is highly relevant t the mission of the Department of Veterans Affairs. That success will be a significant impetus to extend the radiomitigation concept to other normal tissues at risk during radiation therapy, such as spinal cord or brain.