Mitigation of Radiation Pneumonitis and Fibrosis

描述（由申请人提供）： 该项目将测试依那普利（一种血管紧张素转换酶抑制剂）在接受肺癌放射治疗的退伍军人中减轻放射性肺炎和纤维化的效果。它是基于人体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性刺激研究。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.测试的好处 依那普利，一种血管紧张素转化酶抑制剂，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开始照射后立即开始， 接受放射治疗的病人 肺癌的治疗，以及它们对放射性肺炎和纤维化的影响将进行比较。 将使用依那普利而不是卡托普利，因为依那普利是每日单次给药。 2.探讨依那普利减轻放射性肺损伤的机制。 a.血管紧张素原、血浆肾素活性和血管紧张素II 将作为所有受试者的肾素-血管紧张素系统标志物进行测量。 B.与安慰剂相比，将评估依那普利对每种标志物的影响。 3.确认依那普利在此用途中不会对癌症治疗结果产生不利影响。 a.将比较依那普利组和安慰剂组的癌症复发和癌症死亡。 这些研究将在接受肺癌放射治疗的男性和女性中进行。依那普利或外观相同的安慰剂将在放射治疗开始时开始。依那普利或安慰剂的作用将通过其对2级或更高临床放射性肺炎的作用，通过其对肾素-血管紧张素系统标志物血管紧张素原、血浆肾素活性、血管紧张素II的作用，以及其对肺炎和纤维化的放射学证据的作用来测试。 我们工作的广泛，长期目标是实现有效和安全的缓解任何组织类型的正常组织辐射损伤。我们和其他人已经成功地减轻了正常组织辐射损伤（NTRI）的肾脏，肺，皮肤和大脑，使用实验室大鼠模型。这些人体研究的成功将对肺部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状况，这与退伍军人事务部的使命高度相关。这一成功将成为将放射治疗概念扩展到放射治疗期间面临风险的其他正常组织（例如脊髓或大脑）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.