Abstract
Non-targeted effects (NTE) such as bystander effects or genomic instability have been known for many years but their significance for radiotherapy or medical diagnostic radiology are far from clear. Central to the issue are reported differences in the response of normal and tumour tissues to signals from directly irradiated cells. This review will discuss possible mechanisms and implications of these different responses and will then discuss possible new therapeutic avenues suggested by the analysis. Finally, the importance of NTE for diagnostic radiology and nuclear medicine which stems from the dominance of NTE in the low-dose region of the dose–response curve will be presented. Areas such as second cancer induction and microenvironment plasticity will be discussed.
Highlights
Introduction to Modern Studies of radiation-induced bystander effects (RIBE)A series of early experiments by Jolles [10,21] determined that a bystander-like effect can be observed by examining surrounding tissue of an area exposed to X-rays
Seymour et al described so-called “lethal mutations” in 1986, Pampfer and Streffer described an in vivo type of genomic instability in 1989 and Kadhim et al showed the appearance of delayed non-clonal chromosomal instability in 1992 [11,23,24]
MAPK pathway, TGFβ binding to TGFβR—its associated cell membrane receptor—can lead to the downstream indirect phosphorylation of p38 (MAPK14) further down the cascade [59,60,61,83,84], which can lead to p53 activation [59,60,61]; activation of TRAF2, which is involved in the TNFα pathway, can lead to the same effect [59,60,61,85]
Summary
Marcus Tullius Cicero, a prolific writer, orator, and conservative Roman senator, wrote a rather flowery Latin phrase in “On the Contempt of Death” roughly translating to “I am not ashamed to confess that I am ignorant of what I do not know” (Tusculanae Disputationes) in the years that encapsulated the death throes of the Roman Republic. Before discussing the contemporary field of radiation biology in relation to the likely relevance for radiation oncology and diagnostic radiology, it is important to understand the historical context of radiobiological research with regard to the different kinds of indirect radiation effects, the DNA-centric paradigm, and radiation-induced bystander effects (RIBE) Insight into these subjects in a historical context can provide invaluable knowledge for the study of the interaction between radiation and living systems. Up until about forty years ago, it was widely assumed that radiation acts on cells primarily through interacting with DNA [1] This was a convenient model for determining the effects of ionizing radiation on cells, with researchers usually following a model involving direct damage to chromosomes, usually at high doses [1,2]. Cancers 2019, 11, 1236 dating from the 1930s to the 1980s; as stated in Mothersill et al [3], “genes were perfect cellular targets [of radiation] and with the discovery of DNA structure, everything seemed to fit and the “inconvenient truths (of radiobiological effects) were ignored”
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