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Oxidative damage pathways in relation to normal tissue injury

Departments of ¹ Radiation Oncology, Neurosurgery and Cancer Biology, Brain Tumor Center of Excellence and ² Hypertension & Vascular Disease Center, General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

Correspondence: Mike E Robbins, Room # 409 NRC, Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. E-mail: mrobbins{at}wfubmc.edu

Given the increasing population of long-term cancer survivors, the need to mitigate or treat late effects has emerged as a primary area of radiation biology research. Once thought to be irreversible, radiation-induced late effects are now viewed as dynamic multicellular interactions between multiple cell types within a particular program that can be modulated. The molecular, cellular and biochemical pathways responsible for radiation-induced late morbidity remain ill-defined. This review provides data in support of the hypothesis that these late effects are driven, in part, by a chronic oxidative stress. Irradiating late responding normal tissues leads to chronic increases in reactive oxygen/reactive nitrogen oxide species that serve as intracellular signaling species to alter cell function/phenotype, resulting in chronic inflammation, organ dysfunction, and ultimate fibrosis and/or necrosis. Furthermore, we hypothesize that the effectiveness of renin-angiotensin system blockers in preventing or mitigating the severity of radiation-induced late effects reflects, in part, inhibition of reactive oxygen species generation and the resultant chronic oxidative stress. These findings provide a robust rationale for anti-inflammatory-based interventional therapies in the treatment of late normal tissue injury.

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