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.

Public Health Relevance

This project will test the effect of enalapril to mitigate the lung damage that can occur as a side effect of radiation therapy for lung cancer. Thousands of veterans develop lung cancer every year, and are treated by radiation therapy. Studies of lung radiation injury in laboratory animals show that with enalapril, we can significantly reduce the severity of radiation injury to the lung. Enalapril is FDA approved and in common use for treatment of hypertension, kidney disease, and heart failure. These studies will advance that work to human use. Successful mitigation of lung radiation damage will improve the quality of life in veterans and non-veterans who are treated for lung cancer by radiation, and may also improve cure rates of radiation therapy for lung cancer.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Clinical Trials (CLIN)
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Clement J. Zablocki VA Medical Center
United States
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Citrin, Deborah E; Prasanna, Pataje G S; Walker, Amanda J et al. (2017) Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res 188:1-20
Finkel, Kevin W; Cohen, Eric P; Shirali, Anushree et al. (2016) Paraprotein-Related Kidney Disease: Evaluation and Treatment of Myeloma Cast Nephropathy. Clin J Am Soc Nephrol 11:2273-2279
Cohen, Eric P; Krzesinski, Jean-Marie; Launay-Vacher, Vincent et al. (2015) Onco-nephrology: Core Curriculum 2015. Am J Kidney Dis 66:869-83