Wurzer G, Herceg Z, Wesierska-Gadek J
Institute of Cancer Research, University of Vienna, Austria.
Cancer Res. 2000 Aug 1;60(15):4238-44.
Mouse embryo fibroblasts lacking poly(ADP-ribose) polymerase (PARP)-1 express a barely detectable level of wild-type (wt) p53 protein. Doxorubicin at concentrations activating wt p53 in normal mouse embryo fibroblasts failed to induce it in mutant cells. wt p53 was only activated in response to a 10-fold higher doxorubicin dose. Treatment with higher doxorubicin concentrations was cytotoxic for normal but not for PARP-1 -/- cells. The latter was also resistant to other anticancer agents. The increased resistance of mutant cells to drugs resembled a unique phenomenon known as multidrug resistance (MDR). Interestingly, the MDR gene product P-glycoprotein was clearly up-regulated in PARP-1-deficient cells as compared with normal counterparts. Pretreatment with verapamil reversed the MDR phenotype.
缺乏聚（ADP - 核糖）聚合酶（PARP）-1的小鼠胚胎成纤维细胞表达的野生型（wt）p53蛋白水平几乎检测不到。在正常小鼠胚胎成纤维细胞中能激活wt p53的阿霉素浓度，在突变细胞中却无法诱导其表达。wt p53仅在阿霉素剂量高出10倍时才被激活。用更高浓度的阿霉素处理对正常细胞具有细胞毒性，但对PARP - 1基因敲除细胞则无毒性。后者对其他抗癌药物也具有抗性。突变细胞对药物抗性的增加类似于一种被称为多药耐药性（MDR）的独特现象。有趣的是，与正常细胞相比，MDR基因产物P - 糖蛋白在PARP - 1缺陷细胞中明显上调。用维拉帕米预处理可逆转MDR表型。
