P53-DEPENDENT APOPTOSIS MODULATES THE CYTOTOXICITY OF ANTICANCER AGENTS
P53-DEPENDENT APOPTOSIS MODULATES THE CYTOTOXICITY OF ANTICANCER AGENTS
复制标题
DOI：
10.1016/0092-8674(93)90719-7
复制
发表时间：
1993-09-24
期刊：
影响因子：
64.5
通讯作者：
HOUSMAN, DE
中科院分区：
文献类型：
--
作者：
LOWE, SW;RULEY, HE;HOUSMAN, DE
虽然许多抗癌药物的主要细胞靶点已经确定，但对导致癌细胞选择性细胞死亡的过程或耐药的分子基础知之甚少。利用p53基因缺陷的小鼠胚胎成纤维细胞，系统地检测了细胞对不同抗癌药的敏感性和耐药性对p53的需求。这些结果表明，癌基因，特别是腺病毒E1a基因，可以使成纤维细胞对电离辐射、5-氟尿嘧啶、依托泊苷和阿霉素诱导的细胞凋亡敏感。此外，p53肿瘤抑制因子是有效执行死亡程序所必需的。这些数据强化了许多抗癌药的细胞毒作用涉及药物和细胞靶点相互作用后的过程的概念，并表明不同的刺激可以激活共同的细胞死亡程序。因此，p53参与了细胞的凋亡反应，提示了肿瘤细胞对抗癌药物产生交叉耐药的机制。
Although the primary cellular targets of many anticancer agents have been identified, less is known about the processes leading to the selective cell death of cancer cells or the molecular basis of drug resistance. p53-deficient mouse embryonic fibroblasts were used to examine systematically the requirement for p53 in cellular sensitivity and resistance to a diverse group of anticancer agents. These results demonstrate that an oncogene, specifically the adenovirus E1A gene, can sensitize fibroblasts to apoptosis induced by ionizing radiation, 5-fluorouracil, etoposide, and adriamycin. Furthermore, the p53 tumor suppressor is required for efficient execution of the death program. These data reinforce the notion that the cytotoxic action of many anticancer agents involves processes subsequent to the interaction between drug and cellular target and indicate that divergent stimuli can activate a common cell death program. Consequently, the involvement of p53 in the apoptotic response suggests a mechanism whereby tumor cells can acquire cross-resistance to anticancer agents.