Potential molecular targets for manipulating the radiation response.
Recent advances in our understanding of the molecular events that occur following ionizing radiation leading to DNA damage and repair, apoptosis, and cell-cycle arrests suggest new ways in which the radiation response might be manipulated. Specific targets which, if inactivated, might increase radiosensitivity include Ras, which has been implicated in the radioresistant phenotype, and components of DNA-dependent protein kinase or other molecules involved in the recognition or repair of DNA damage. In some tumors, apoptosis is an important mode of cell death following radiation, so agents that promote this may prove useful therapeutically. Conversely, side effects may result from radiation-induced apoptosis of normal tissues: for example, pneumonitis following the destruction of endothelial cells in the pulmonary vasculature. Therefore, decreasing apoptosis in these tissues may reduce late effects. It may also be possible to prevent late effects such as fibrosis by blocking the induction of certain genes such as transforming growth factor beta. Cell-cycle regulation is another area that could be manipulated to increase radiosensitivity. There is evidence that the G2 delay following radiation is important in protecting cells from death. Abolition of this delay may increase radiosensitivity, especially in cells with mutant p53 that have lost the G1 checkpoint.
Maity
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Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, USA.
Kao
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GD
Muschel
R J
RJ
McKenna
W G
WG
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D002453:Cell Cycle / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004789:Enzyme Activation; D015870:Gene Expression / Q000528:radiation effects*; D017781:Genes, Immediate-Early / Q000528:radiation effects; D006801:Humans; D009857:Oncogenes / Q000528:radiation effects; D011493:Protein Kinase C / Q000378:metabolism; D011519:Proto-Oncogenes / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects*
D011493:Protein Kinase C