Maity A, Kao G D, Muschel R J, McKenna W G
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, USA.
Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):639-53. doi: 10.1016/s0360-3016(96)00598-6.
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.
我们对电离辐射后导致DNA损伤与修复、细胞凋亡及细胞周期停滞的分子事件的理解取得了新进展，这提示了操控辐射反应的新方法。若失活可能会增加放射敏感性的特定靶点包括Ras（其与放射抗性表型有关）以及DNA依赖性蛋白激酶的组分或参与DNA损伤识别或修复的其他分子。在一些肿瘤中，细胞凋亡是辐射后细胞死亡的重要模式，因此促进细胞凋亡的药物可能具有治疗作用。相反，正常组织的辐射诱导凋亡可能会产生副作用：例如，肺血管内皮细胞被破坏后引发的肺炎。因此，减少这些组织中的细胞凋亡可能会减轻后期效应。通过阻断某些基因（如转化生长因子β）的诱导，也有可能预防诸如纤维化等后期效应。细胞周期调控是另一个可操控以提高放射敏感性的领域。有证据表明，辐射后的G2期延迟对于保护细胞免于死亡很重要。消除这种延迟可能会增加放射敏感性，尤其是在具有突变p53且已失去G1期检查点的细胞中。
