Mueller H, Eppenberger U
Department of Gynecology, University Hospital Basel, Switzerland.
Anticancer Res. 1996 Nov-Dec;16(6B):3845-8.
Mutational loss of p53 tumor suppressor functions has been observed in a wide range of neoplasms and was associated with either enhanced or decreased chemosensitivity of affected tumors. The dual role of wild-type p53 as a DNA repair initiator and a trigger for apoptosis raises the possibility that appropriately designed chemotherapy could be selectively applied against p53-defective tumor cells. The cytotoxic effects of DNA-crosslinking chemotherapeutica such as cisplatin could be enhanced by mutated p53 which is no longer able to repair drug-induced DNA damage. In contrast, DNA synthesis blockers such as fluorouracil can induce apoptosis through p53-dependent mechanisms. Thus, loss of p53 functions results in decreased sensitivity to this type of drugs. Clinical studies will reveal the role of abberant p53 in the efficacy of chemotherapy for individual patients.
在多种肿瘤中都观察到了p53肿瘤抑制功能的突变性缺失，这与受影响肿瘤的化疗敏感性增强或降低有关。野生型p53作为DNA修复启动子和细胞凋亡触发因子的双重作用，增加了这样一种可能性，即经过适当设计的化疗可以选择性地应用于p53缺陷的肿瘤细胞。DNA交联化疗药物（如顺铂）的细胞毒性作用可被不再能够修复药物诱导的DNA损伤的突变型p53增强。相反，DNA合成阻滞剂（如氟尿嘧啶）可通过p53依赖性机制诱导细胞凋亡。因此，p53功能的丧失导致对这类药物的敏感性降低。临床研究将揭示异常p53在个体患者化疗疗效中的作用。
