The goal of this project is to use rodent models to study the mechanism of late radiation-induced tissue injury. The proposal is based on the discovery that radiation nephropathy is a major complication of the total body irradiation used in bone marrow transplantation (BMT), that the rat is an excellent model for this nephropathy, and the discovery that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) blockers could be used to treat BMT nephropathy. The studies are strongly influenced by the finding that ACE inhibitors and AII blockers can permanently interfere with the development of BMT nephropathy even when treatment is started after irradiation and is not continued indefinitely. These findings cast doubt on the standard mechanistic explanations for late radiation injury, and open up the possibility that normal tissue radiation injuries can be treated, or even prevented, by post-irradiation interventions.
The specific aims of this proposal are: 1) To test the hypothesis that radiation-induced activation of the renin-angiotensin system (RAS) is the cause of radiation (and BMT) nephropathy. 2) To test the hypothesis that fibrosis is a cause , rather than a consequence , of radiation nephropathy. 3) To test the hypothesis that AT1 receptor antagonists are preferentially effective in the prophylaxis and treatment of radiation (and BMT) nephropathy. 4) To retrospectively assess the factors influencing the incidence of BMT nephropathy in humans. 5) To determine in a prospective randomized clinical trial whether captopril can be used to lower the incidence of BMT nephropathy. 6) To determine the basis for the dependence of renal tolerance on age-at-irradiation, and whether the change in tolerance is related to the decreased effectiveness of ACE inhibitors in older animals. 7) To determine the conditions under which pulsed low dose rate (LDR) and continuous LDR produce clinically equivalent normal tissue injury.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024652-21
Application #
6124427
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1979-01-01
Project End
2001-11-30
Budget Start
1999-12-03
Budget End
2000-11-30
Support Year
21
Fiscal Year
2000
Total Cost
$240,438
Indirect Cost
Name
Medical College of Wisconsin
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073134603
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
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
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 (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
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
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

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