Throughout the review, the synergy of combined "omics" technologies such as genomics and epigenomics, proteomics, and metabolomics is highlighted. These are anticipated to lead to new hypotheses to understand IR effects on biological systems and improve IR-based therapies.

The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) gamma agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.

Although a causal link between chronic oxidative stress and radiation-induced late normal tissue injury remains to be established, a growing body of evidence appears to support the hypothesis that chronic oxidative stress might serve to drive the progression of radiation-induced late effects. The similarity between chronic tissue injury, chronic inflammation and fibrosis observed in a variety of disease states, including radiation late effects, is provocative and offers the opportunity to apply antioxidant-based therapies to mitigate and/or treat late radiation-induced normal tissue injury.

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.

Protein sulfenic acids are formed by the reaction of biologically relevant reactive oxygen species with protein thiols. Sulfenic acid formation modulates the function of enzymes and transcription factors either directly or through the subsequent formation of protein disulfide bonds. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1,3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, the present study describes highly strained bicyclo[6.1.0]nonyne (BCN) derivatives as concerted traps of sulfenic acids. These strained cycloalkynes react efficiently with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100× greater than 1,3-dicarbonyl reagents enabling kinetic competition with physiological sulfur chemistry. Similar to the 1,3-dicarbonyl reagents, the BCN compounds distinguish the sulfenic acid oxoform from the thiol, disulfide, sulfinic acid, and S-nitrosated forms of cysteine while displaying an acceptable cell toxicity profile. The enhanced rates demonstrated by these strained alkynes identify them as new bioorthogonal probes that should facilitate the discovery of previously unknown sulfenic acid sites and their parent proteins.