This project is based on the hypothesis that late radiation-induced normal tissue injuries can be prevented and/or treated with post-irradiation pharmacologic intervention. The rat radiation nephropathy model is used to study the pathophysiological mechanism(s) of late radiation-induced normal tissue injuries, and these mechanistic understandings are used in the development of methods for prophylaxis and treatment of these injuries. The discovery that radiation nephropathy is a major complication of bone marrow transplantation (BMT) conditioning, and that the rat was an excellent model for this nephropathy, added a preclinical component to the project. The discovery that angiotensin converting enzyme (ACE) inhibitors and an angiotensin II (AII) blockers could be used for the prophylaxis and treatment of BMT nephropathy led directly to clinical studies. The studies are strongly influenced by the finding that blocking the renin-angiotensin system can permanently interfere with the development of radiation nephropathy even when treatment is started weeks after irradiation and/or is not continued indefinitely. These latter findings cast considerable doubt on the standard mechanistic explanations for late radiation injuries, and suggest that injuries caused by radiation therapy, radiation accidents or nuclear terrorism could be treated or prevented with post-irradiation pharmacological interventions.
The specific aims of this proposal fall into four related groups: ? 1) Refute the hypothesis that radiation-induced activation of the renin-angiotensin system is the proximal mechanistic cause of radiation nephropathy. ? 2) Confirm the hypothesis that prophylaxis and treatment of radiation nephropathy with ACE inhibitors and AII blockers operate by different mechanisms. ? 3) Determine the mechanistic basis for the efficacy of ACE inhibitors and AII receptor blockers in the prophylaxis of radiation nephropathy. ? 4) Complete the randomized, prospective, trial of the use of ACE inhibitors to prevent the development of radiation nephropathy in BMT patients. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024652-26
Application #
7009585
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1979-01-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
26
Fiscal Year
2006
Total Cost
$309,795
Indirect Cost
Name
Medical College of Wisconsin
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Cohen, Eric P; Bedi, Manpreet; Irving, Amy A et al. (2012) Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation. Int J Radiat Oncol Biol Phys 83:292-6
Moulder, John E; Cohen, Eric P; Fish, Brian L (2011) Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation. Radiat Res 175:29-36
Lenarczyk, Marek; Cohen, Eric P; Fish, Brian L et al. (2009) Chronic oxidative stress as a mechanism for radiation nephropathy. Radiat Res 171:164-72
Cohen, Eric P; Fish, Brian L; Irving, Amy A et al. (2009) Radiation nephropathy is not mitigated by antagonists of oxidative stress. Radiat Res 172:260-4
Cohen, Eric P (2008) HIPAA threatens clinical research. Ann Diagn Pathol 12:311-2
Cohen, Eric P; Irving, Amy A; Drobyski, William R et al. (2008) Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: a randomized controlled trial. Int J Radiat Oncol Biol Phys 70:1546-51
Cohen, Eric P; Fish, Brian L; Sharma, Mukut et al. (2007) Role of the angiotensin II type-2 receptor in radiation nephropathy. Transl Res 150:106-15
Moulder, John E; Cohen, Eric P (2007) Renal dysfunction after total body irradiation: dose-effect relationship: in regard to Kal and van Kempen-Harteveld (Int J Radiat Oncol Biol Phys 2006;65:1228-1232). Int J Radiat Oncol Biol Phys 67:319;author reply 319-20
Moulder, J E; Fish, B L; Cohen, E P (2007) Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists. Curr Pharm Des 13:1317-25
Moulder, John E; Cohen, Eric P (2007) Future strategies for mitigation and treatment of chronic radiation-induced normal tissue injury. Semin Radiat Oncol 17:141-8

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