Moll U M, Ostermeyer A G, Ahomadegbe J C, Mathieu M C, Riou G
Department of Pathology, State University of New York, Stony Brook 11794-8691, USA.
Hum Pathol. 1995 Dec;26(12):1293-301. doi: 10.1016/0046-8177(95)90292-9.
Wild type p53 plays a crucial role in maintaining genomic stability in both normal and tumor cells in vitro. When DNA damage occurs, p53 acts as a cell cycle checkpoint and induces a cellular response that aims at restoring genomic integrity. p53 may either allow the repair of damaged DNA by inducing a transient G1 arrest or may eliminate the damaged cells by triggering apoptosis. Mutant p53 fails to mediate any of these effects. From this, a p53 status-dependent response to therapy might be expected when tumors are treated with DNA-damaging genotoxic agents: Although wild type p53-harboring tumors have an intact checkpoint that might allow them to restore genomic integrity back to a pre-exposure level, mutant p53 tumors have a corrupted checkpoint that could lead to an accelerated loss of genomic stability. Until now, no studies have been described that examine such a p53-mediated effect in vivo. The authors tested this response model in vivo comparing 32 matched biopsy pairs from patients with breast cancer before and after rigorously standardized polychemotherapy. Four of the five drugs specifically induce a wild type p53-mediated checkpoint response. Tumor tissue from matched pairs of untreated and treated biopsies of the same patient were analyzed for treatment-associated changes of p53 protein expression by immunocytochemistry and, in a few available specimens, of p53 genotype changes by polymerase chain reaction-based DNA analysis. Treatment-associated changes of the p53 immunophenotype, which the authors speculate to reflect clonal selection, occurred in 39% (12 of 31) of the specimens. One specimen was not informative. Most tumors undergoing clonal selection originally harbored mutant p53 (nine of 12), and only three of 12 tumors were wild type. This study shows that exposure to genotoxic agents is commonly associated with a change in p53 immunophenotype. Although the limited material in this cohort prevented direct analysis of genetic instability, these results suggest that tumors with altered p53 may be genomically less stable and, therefore, may be more likely to undergo treatment-induced clonal changes than wild type tumors. This study also shows that the rigorous matched sample approach, although difficult to obtain, is an important tool that allows the in vivo assessment of the tumor response to genotoxic therapy in a controlled fashion.
野生型p53在体外维持正常细胞和肿瘤细胞的基因组稳定性方面起着关键作用。当DNA损伤发生时，p53作为细胞周期检查点并诱导旨在恢复基因组完整性的细胞反应。p53既可以通过诱导短暂的G1期阻滞来允许受损DNA的修复，也可以通过触发凋亡来消除受损细胞。突变型p53无法介导这些效应中的任何一种。由此推测，当肿瘤用DNA损伤性基因毒性药物治疗时，可能会出现p53状态依赖性的治疗反应：虽然携带野生型p53的肿瘤具有完整的检查点，这可能使它们能够将基因组完整性恢复到暴露前水平，但突变型p53肿瘤的检查点已受损，这可能导致基因组稳定性加速丧失。到目前为止，尚未有研究描述在体内检测这种p53介导的效应。作者在体内测试了这种反应模型，比较了来自乳腺癌患者的32对匹配活检样本在严格标准化多药化疗前后的情况。五种药物中的四种特异性诱导野生型p53介导的检查点反应。通过免疫细胞化学分析同一患者未经治疗和治疗后的活检匹配对的肿瘤组织中p53蛋白表达的治疗相关变化，并在少数可用标本中通过基于聚合酶链反应的DNA分析检测p53基因型变化。作者推测反映克隆选择的p53免疫表型的治疗相关变化发生在39%（31个样本中的12个）的标本中。一个标本无信息。大多数经历克隆选择的肿瘤最初携带突变型p53（12个中的9个），1个中的3个肿瘤为野生型。这项研究表明，暴露于基因毒性药物通常与p53免疫表型的变化有关。尽管该队列中的材料有限，无法直接分析遗传不稳定，但这些结果表明，p53改变的肿瘤在基因组上可能不太稳定，因此，与野生型肿瘤相比，可能更有可能经历治疗诱导的克隆变化。这项研究还表明，严格的匹配样本方法虽然难以获得，但却是一种重要工具，它能够以可控方式在体内评估肿瘤对基因毒性治疗的反应。
