Abstract
Significance: Radiation therapy (from external beams to unsealed and sealed radionuclide sources) takes advantage of the detrimental effects of the clustered production of radicals and reactive oxygen species (ROS). Research has mainly focused on the interaction of radiation with water, which is the major constituent of living beings, and with nuclear DNA, which contains the genetic information. This led to the so-called target theory according to which cells have to be hit by ionizing particles to elicit an important biological response, including cell death. In cancer therapy, the Poisson law and linear quadratic mathematical models have been used to describe the probability of hits per cell as a function of the radiation dose.Recent Advances: However, in the last 20 years, many studies have shown that radiation generates “danger” signals that propagate from irradiated to nonirradiated cells, leading to bystander and other off-target effects.Critical Issues: Like for targeted effects, redox mechanisms play a key role also in off-target effects through transmission of ROS and reactive nitrogen species (RNS), and also of cytokines, ATP, and extracellular DNA. Particularly, nuclear factor kappa B is essential for triggering self-sustained production of ROS and RNS, thus making the bystander response similar to inflammation. In some therapeutic cases, this phenomenon is associated with recruitment of immune cells that are involved in distant irradiation effects (called “away-from-target” i.e., abscopal effects).Future Directions: Determining the contribution of targeted and off-target effects in the clinic is still challenging. This has important consequences not only in radiotherapy but also possibly in diagnostic procedures and in radiation protection.
Highlights
For about one century, the paradigm of radiation biology has been that cells need to be traversed by radiation to be killed
We presented in an analytical way the current status of knowledge in the area of off-target and awayfrom-target ionizing radiation effects with special emphasis on their role on radiation therapy and clinical applications
After years of intensive in vitro and in vivo research and circumstantial clinical evidence in humans, the idea of offtarget effects has gained high interest and is increasingly accepted by the scientific community. It is certainly considered a paradigm shift from the target theory in radiation biology where biological important components of the cells must be directly hit from radiation to show a radiation response
Summary
The paradigm of radiation biology has been that cells need to be traversed by radiation to be killed. In the context of the ‘‘targeted effects’’ of radiation, most research has focused on DNA because it was considered to be the main if not the only target. In the 1990s, a shift in the radiation biology paradigm occurred on the basis of the observation that biological effects could be observed after irradiation of non-nuclear cell compartments [248, 276, 335]. The existence of dynamic signaling pathways between the various subcellular compartments (nucleus, endoplasmic reticulum [ER], mitochondria, and cell membrane) needs to be taken into account when assessing radiation-induced effects. We discuss the currently available models to predict the therapeutic efficacy and side effects of radiation exposure by taking into account both targeted and off-target effects
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