The NCI has identified long-term survival from cancer as one of the new areas of public health emphasis; the late effects of cancer treatments are of particular importance. Progressive dementia occurs in some 20-50% of brain tumor patients who are long-term survivors after treatment with brain irradiation. The need to both understand and minimize the side effects of brain irradiation is exacerbated by the ever- increasing number of patients with brain metastases that require treatment with large field or whole brain irradiation (WBI); some 200,000 cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. Data support a role for the renin-angiotensin system (RAS) in radiation-induced late effects in kidney, lung; both angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) receptor antagonists (ATRA) have proved effective. However, the pathogenic mechanism(s) involved remains unknown. Recent studies have identified a functioning RAS in the brain that is involved in cognition, memory, anxiety and stress. We hypothesize that WBI upregulated the intrinsic brain RAS, leading to a chronic and persistent oxidative stress/inflammatory response that results in the development and progression of radiation-induced brain injury, including cognitive impairment. To test this hypothesis we will pursue the following in vitro and in vivo Specific Aims:
In Aims 1 and 2 we will test the hypothesis that inhibiting Ang II in normal brain cells will reduce the severity of pro-inflammatory changes in brain cell phenotype and/or function. We will use well-defined models of primary rat astrocytes, rat brain microvascular endothelial cells and rat microglia.
In aims 3 and 4 we will test the hypothesis that inhibiting the intrinsic brain RAS using RAS blockers targeted at either ACE (ACEI), or the Ang II receptors (AT1RA and AT2RA) will ameliorate the development and progression of radiation-induced brain injury in vivo. Rats will receive a clinically relevant fractionated course of WBI, and acute (Specific Aim 3) and chronic (Specific Aim 4) changes in components of the RAS and pro-inflammatory mediators will be determined, as well as chronic changes in cognitive function. The establishment of an interventional role for Ang II blockers in modulating radiation-induced brain injury should lead to the rapid translation of these findings to the clinic, with the promise of increasing the therapeutic window for cancer patients receiving large field or WBI as well as improving their quality of life. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122318-03
Application #
7485698
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Stone, Helen B
Project Start
2006-08-07
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$247,327
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Greene-Schloesser, Dana M; Kooshki, Mitra; Payne, Valerie et al. (2014) Cellular response of the rat brain to single doses of (137)Cs ? rays does not predict its response to prolonged 'biologically equivalent' fractionated doses. Int J Radiat Biol 90:790-8
Moore, Elizabeth D; Kooshki, Mitra; Metheny-Barlow, Linda J et al. (2013) Angiotensin-(1-7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling. Free Radic Biol Med 65:1060-1068
Greene-Schloesser, Dana; Moore, Elizabeth; Robbins, Mike E (2013) Molecular pathways: radiation-induced cognitive impairment. Clin Cancer Res 19:2294-300
Greene-Schloesser, Dana; Robbins, Mike E (2012) Radiation-induced cognitive impairment--from bench to bedside. Neuro Oncol 14 Suppl 4:iv37-44
Lee, Tammy C; Greene-Schloesser, Dana; Payne, Valerie et al. (2012) Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res 178:46-56
Robbins, Mike E; Brunso-Bechtold, Judy K; Peiffer, Ann M et al. (2012) Imaging radiation-induced normal tissue injury. Radiat Res 177:449-66
Gilliam-Davis, Shea; Gallagher, Patricia E; Payne, Valerie S et al. (2011) Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components. Physiol Genomics 43:829-35
Conner, Kelly R; Payne, Valerie S; Forbes, M Elizabeth et al. (2010) Effects of the AT1 receptor antagonist L-158,809 on microglia and neurogenesis after fractionated whole-brain irradiation. Radiat Res 173:49-61
Robbins, M E; Zhao, W; Garcia-Espinosa, M A et al. (2010) Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets 11:1413-22

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