Replication-Competent Ad11p Vector (RCAd11p) Efficiently Transduces and Replicates in Hormone-Refractory Metastatic Prostate Cancer Cells
Replication-Competent Ad11p Vector (RCAd11p) Efficiently Transduces and Replicates in Hormone-Refractory Metastatic Prostate Cancer Cells
复制标题
DOI：
10.1089/hum.2007.124
复制
发表时间：
2009-04-01
影响因子：
4.2
通讯作者：
Mei, Ya-Fang
中科院分区：
文献类型：
--
作者：
Sandberg, Linda;Papareddy, Praveen;Mei, Ya-Fang
选择性可复制腺病毒血清型5载体已用于前列腺癌治疗。不幸的是，基因转移是低效的，因为难治性转移性前列腺癌细胞具有最小的柯萨奇病毒-腺病毒受体表达。基于种B腺病毒的载体是用于人类基因治疗的有吸引力的工具，因为病毒具有低血清阳性率并且它们具有有效的转导能力。大多数种B腺病毒使用普遍表达的补体调节性CD 46蛋白作为细胞受体。在这里，我们报告的转导效率和溶瘤能力的复制能力Ad 11 p（RCAd 11 p）载体在人前列腺癌细胞。绿色荧光蛋白以剂量依赖性方式分别在来源于前列腺癌骨转移和脑转移的PC-3和DU 145细胞中有效表达。然而，转导在来源于前列腺癌转移到淋巴结的LNCaP细胞中不太有效。RCAd 11 p载体的溶瘤能力在PC-3细胞中比在其他两种细胞系中高100倍。溶瘤作用与细胞中p53的表达水平或载体中E1 B55 k表达的缺乏无关。体内实验显示，与未处理的对照组相比，用RCAd 11 p载体或Ad 11 pwt处理的异种移植小鼠组中PC-3肿瘤的生长受到显著抑制。因此，我们已经证明了RCAd 11 p载体固有地具有溶瘤特性，其在靶向肿瘤细胞中是有活性的。因此，新型RCAd 11 p载体具有治疗不可治愈的转移性前列腺疾病的巨大潜力。
Selective replication-competent adenovirus serotype 5 vectors have been used for prostate cancer therapy. Unfortunately, gene transfer is inefficient because hormone-refractory metastatic prostate cancer cells have minimal coxsackievirus-adenovirus receptor expression. Vectors based on species B adenoviruses are attractive tools for use in human gene therapy because the viruses have low seroprevalence and they have efficient transduction capacity. Most species B adenoviruses use ubiquitously expressed complement-regulatory CD46 protein as a cellular receptor. Here we report the transduction efficacy and oncolytic capacity of a replication-competent Ad11p (RCAd11p) vector in human prostate cancer cells. Green fluorescent protein was efficiently expressed in a dose-dependent manner in PC-3 and DU 145 cells derived from metastasis of prostate cancer to bone and brain, respectively. However, transduction was less effective in LNCaP cells derived from prostate cancer metastasis to lymph nodes. The oncolytic capacity of the RCAd11p vector was 100 times higher in PC-3 cells than in the two other cell lines. The oncolysis was independent of the level of expression of p53 in the cells or on the absence of E1B55k expression in the vector. In vivo experiments revealed significant growth inhibition of PC-3 tumors in the xenograft mouse group treated with RCAd11p vector or Ad11pwt in comparison with the untreated control group. Thus, we have demonstrated that RCAd11p vector intrinsically possesses oncolytic properties, which were active in targeting tumor cells. Consequently, the novel RCAd11p vector has great potential for the treatment of incurable metastatic prostate disease.