Bristow R G, Benchimol S, Hill R P
Department of Radiation Oncology, University of Toronto, Canada.
Radiother Oncol. 1996 Sep;40(3):197-223. doi: 10.1016/0167-8140(96)01806-3.
Experimental studies have implicated the normal or "wild type' p53 protein (i.e. WTp53) in the cellular response to ionizing radiation and other DNA damaging agents. Whether altered WTp53 protein function can lead to changes in cellular radiosensitivity and/or clinical radiocurability remains an area of ongoing study. In this review, we describe the potential implications of altered WTp53 protein function in normal and tumour cells as it relates to clinical radiotherapy, and describe novel treatment strategies designed to re-institute WTp53 protein function as a means of sensitizing cells to ionizing radiation.
A number of experimental and clinical studies are critically reviewed with respect to the role of the p53 protein as a determinant of cellular oncogenesis, genomic stability, apoptosis, DNA repair and radioresponse in normal and transformed mammalian cells.
In normal fibroblasts, exposure to ionizing radiation leads to a G1 cell cycle delay (i.e. a "G1 checkpoint') as a result of WTp53 mediated inhibition of G1-cyclin-kinase and retinoblastoma (pRb) protein function. The G1 checkpoint response is absent in tumour cells which express a mutant form of the p53 protein (i.e. MTp53), leading to acquired radioresistance in vitro. Depending on the cell type studied, this increase in cellular radiation survival can be mediated through decreased radiation-induced apoptosis, or altered kinetics of the radiation-induced G1 checkpoint. Recent biochemical studies support an indirect role for the p53 protein in both nucleotide excision and recombinational DNA repair pathways. However, based on clinicopathologic data, it remains unclear as to whether WTp53 protein function can predict for human tumour radiocurability and normal tissue radioresponse.
Alterations in cell cycle control secondary to aberrant WTp53 protein function may be clinically significant if they lead to the acquisition of mutant cellular phenotypes, including the radioresistant phenotype. Pre-clinical studies suggest that these phenotypes may be reversed using adenovirus-mediated gene therapy or pharmacologic strategies designed to re-institute WTp53 protein function. Our analysis of the published data strongly argues for the use of functional assays for the determination of WTp53 protein function in studies which attempt to correlate normal and tumour tissue radioresponse with p53 genotype, or p53 protein expression.
实验研究表明，正常或“野生型”p53蛋白（即WTp53）参与细胞对电离辐射及其他DNA损伤剂的反应。WTp53蛋白功能改变是否会导致细胞放射敏感性和/或临床放射可治愈性的变化仍是一个正在研究的领域。在本综述中，我们描述了WTp53蛋白功能改变在正常细胞和肿瘤细胞中与临床放射治疗相关的潜在影响，并描述了旨在恢复WTp53蛋白功能以提高细胞对电离辐射敏感性的新治疗策略。
对一些关于p53蛋白在正常和转化哺乳动物细胞中作为细胞肿瘤发生、基因组稳定性、凋亡、DNA修复和放射反应决定因素的作用的实验和临床研究进行了批判性综述。
在正常成纤维细胞中，由于WTp53介导的G1周期蛋白激酶和视网膜母细胞瘤（pRb）蛋白功能抑制，暴露于电离辐射会导致G1细胞周期延迟（即“G1检查点”）。在表达p53蛋白突变形式（即MTp53）的肿瘤细胞中不存在G1检查点反应，导致体外获得放射抗性。根据所研究的细胞类型，细胞辐射存活率的这种增加可通过减少辐射诱导的凋亡或改变辐射诱导的G1检查点动力学来介导。最近的生化研究支持p53蛋白在核苷酸切除和重组DNA修复途径中起间接作用。然而，根据临床病理数据，尚不清楚WTp53蛋白功能是否可以预测人类肿瘤的放射可治愈性和正常组织的放射反应。
如果异常的WTp53蛋白功能导致获得包括放射抗性表型在内的突变细胞表型，那么继发于该功能改变的细胞周期控制改变可能具有临床意义。临床前研究表明，使用腺病毒介导的基因治疗或旨在恢复WTp53蛋白功能的药理学策略可能会逆转这些表型。我们对已发表数据的分析强烈支持在试图将正常和肿瘤组织放射反应与p53基因型或p53蛋白表达相关联的研究中使用功能测定来确定WTp53蛋白功能。
