Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

Abstract

To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

Keywords: Mitigators; Protectors; Radiation normal tissue injury.

Fig. 1

Ionizing radiation causes cell death, both parenchymal and vascular, by multiple mechanisms. Historically, the direct cytotoxicity of radiation was the first identified pathway leading to tissue injury. More recently, another pathway involving inflammation has been identified. A third pathway has been studied in the last few years that implicates the innate immune response including bone marrow-derived cells (BMDC) and both M₁ and M₂ macrophage (MΦ) in resultant tissue damage. Arrows represent influence of one mechanism on another and suggest potential targets for interfering with the process.

Fig. 2

Excessive reactive oxygen species (ROS) derive from multiple sources within the cell and in response to external stimuli (1, cellular membrane ROS predominantly through NADPH oxidase; 2, mitochondrial ROS and reactive nitrogen species through cytochrome C pathway; 3, X-rays passing through the cell interact with water and other cellular molecules to produce ROS). Hydrogen peroxide (H₂O₂) is particularly damaging to cells (green circle) and is produced by all three mechanisms.