Bystander effects of the ionizing radiation and his implications in radiotherapy and radioprotection

According to the classical paradigm, biological effects of ionizing radiation are attributed to DNA damage induced in each irradiated cell. Demonstration of ionizing radiation-induced bystander effects (RIBE) has generated a deep change in current understanding of radiobiology. RIBE are radiation-induced effects produced in cells that have not been actually irradiated. Several technical advances, particularly the use of microbeams, allowed in vitro study of RIBE. There are two known ways by which irradiated cells can communicate with non-irradiated cells, namely: through gap junctions connecting the cytoplasms of adjacent cells, and through the secretion of soluble factors to the extracellular medium. These factors include several cytokines and reactive species of oxygen and nitrogen. In the affected cells, signalling pathways mostly involve activation of mitogen-activated protein kinases (MAPK), NF-kB transcription factor and of the enzymes cyclooxygenase 2, nitric oxide synthase 2 and NAD (P)H oxidase. RIBE induce point mutations and epigenetic changes. Effects on cellular signalling pathways can persist indefinitely and even be transmitted to the progeny of affected cells. Paradoxically, under certain conditions RIBE may be adaptive, which means that they turn affected cells more resistant to ionizing radiation. Adaptation demands protein synthesis. It enhances DNA repair mechanisms and resistance to oxidative stress. RIBE have also been demonstrated in vivo. Thus, they may have important implications for radiotherapy, both to improve therapeutic efficacy and to reduce the incidence of adverse effects. Furthermore, a better understanding of RIBE may have an influence on international radioprotection standards. (authors)