Efficacy of Combination Therapy of Ionizing Radiation and Gene Therapy in Prostate Cancer in vitro

几项研究表明，p53基因的功能是细胞对电离辐射（IR）细胞毒性作用的内在敏感性的主要决定因素之一。此外，将腺病毒介导的野生型p53基因转移与dna损伤治疗（如IR和化疗药物）相结合的策略也已在胶质母细胞瘤、肺癌、结直肠癌、卵巢癌和头颈癌中进行了研究，并且一致观察到额外的细胞毒性或肿瘤抑制活性。在前列腺癌细胞中，重组野生型p53腺病毒（Ad5CMV-p53）的诱导具有显著的细胞毒性。在本研究中，我们评估了IR和Ad5CMV-p53基因治疗在两种雄激素非依赖性前列腺癌细胞系（DU145和PC-3）中的相互作用。我们证明了这种联合治疗产生了显著的协同效应，并评估了其分子机制。Ad5CMV-p53对DU145 （p53突变）细胞的IR抑制作用以病毒剂量依赖性的方式增强。在DU145细胞中，单独IR诱导的p53 mRNA表达极低。然而，IR联合Ad5CMV-p53感染可刺激p53 mRNA表达显著增加，同时Bax和p21 mRNA表达增加。在PC-3 （p53-null）中，IR诱导Bax和p21 mRNA表达，而在p53、Bax和p21 mRNA表达中观察到联合效应。单独IR后很少观察到凋亡细胞死亡（DU145: 3%, PC-3: 5%）。然而，联合治疗后，凋亡细胞比例大幅增加（DU145细胞为7倍，PC-3细胞为2倍）。Ad5CMV-p53感染及合并后，两种细胞系均出现G1细胞周期阻滞。综上所述，Ad5CMV-p53感染通过有效诱导细胞凋亡和细胞周期阻滞来增强放射治疗的效果。这种联合治疗可能是放射耐药前列腺癌的最佳治疗策略之一。少

Several studies have demonstrated that the function of the p53 gene is one of the major determinants of intrinsic cellular sensitivity to the cytotoxic effects of ionizing radiation (IR). Moreover, a strategy to combine adenovirus-mediated wild-type p53 gene transfer with DNA-damaging treatments, such as IR and chemotherapeutic agents, has also been studied in glioblastoma, lung, colorectal, ovarian, and head-and-neck cancers, and additional cytotoxicity or tumor-suppressing activity has been consistently observed. In prostate cancer cells, the significant cytotoxicity has been previously reported with the induction of recombinant wild-type p53 adenovirus (Ad5CMV-p53). In this study, the interactions between IR and Ad5CMV-p53 gene therapy in two androgen-independent prostate cancer cell lines (DU145 and PC-3) were evaluated. We demonstrated that this combination therapy resulted in remarkable synergistic effects and also assessed its molecular mechanisms. The cell growth inhibition in … More DU145 (p53-mutated) cells by IR was strongly enhanced by additional Ad5CMV-p53 infection in a viral dose-dependent manner. In DU145 cells, IR alone induced minimal p53 mRNA expression. However, IR combined with Ad5CMV-p53 infection stimulated significant increase in p53 mRNA expression supplemented with Bax and p21 mRNA expressions. In PC-3 (p53-null), IR induced Bax and p21 mRNA expression, while the combination effects were observed in p53, Bax, and p21 mRNA expression. Apoptotic cell deaths were rarely observed after IR alone (DU145: 3%, PC-3: 5%). However, after combination therapy, the proportion of apoptotic cells greatly increased (sevenfold in DU145 cells, and twice in PC-3 cells). G1 cell cycle arrest was observed after Ad5CMV-p53 infection and the combination in both cell lines. In conclusion, Ad5CMV-p53 infection enhances the effect of radiation therapy by efficient induction of apoptosis and cell cycle arrest. This combination therapy could be one of the optimal treatment strategies for radioresistant prostate cancer. Less