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Tumor-specific suicide gene therapy for hepatocellular carcinoma by transcriptionally targeted retroviral replicating vectors

机译：转录靶向逆转录病毒复制载体对肝细胞癌的肿瘤特异性自杀基因治疗

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Replicating virus vectors are attractive tools for anticancer gene therapy, but the potential for adverse events due to uncontrolled spread of the vectors has been a major concern. To design a tumor-specific retroviral replicating vector (RRV), we replaced the U3 region of the RRV ACE-GFP with a regulatory sequence consisting of the hepatitis B virus enhancer II (EII) and human alpha-fetoprotein (AFP) core promoter to produce ACE-GFP-EIIAFP, a hepatocellular carcinoma (HCC)-targeting RRV. Similar to ACE-GFP, ACE-GFP-EIIAFP exhibited robust green fluorescent protein (GFP) expression in HCC cells and, most importantly, it exhibited HCC-specific replication and did not replicate in non-HCC tumor cells or normal liver cells. We sequenced the promoter region of ACE-GFP-EIIAFP collected from serial infection cycles to examine the genomic stability of the vector during its replicative spread, and found that the vector could retain the hybrid promoter in the genome for at least six infection cycles. In vitro studies revealed that ACE-CD-EIIAFP and ACE-PNP-EIIAFP, which express the yeast cytosine deaminase and Escherichia coli purine nucleoside phosphorylase, respectively, exert a highly potent cytotoxic effect on HCC cells in the presence of their respective prodrugs. In vivo, ACE-CD-EIIAFP-mediated suicide gene therapy efficiently suppressed HCC tumor growth and no detectable RRV signal was observed in extratumoral tissues. These results suggest that the tumor-specific, suicide-gene-encoding RRV may fulfill the promise of retroviral gene therapy for cancer.
机译：复制病毒载体是用于抗癌基因治疗的有吸引力的工具，但是由于载体不受控制的扩散而引起的不良事件的可能性已成为主要关注的问题。为了设计肿瘤特异性逆转录病毒复制载体（RRV），我们用由乙型肝炎病毒增强子II（EII）和人甲胎蛋白（AFP）核心启动子组成的调控序列替换了RRV ACE-GFP的U3区，产生ACE-GFP-EIIAFP，一种靶向肝细胞癌（HCC）的RRV。与ACE-GFP相似，ACE-GFP-EIIAFP在HCC细胞中表现出稳定的绿色荧光蛋白（GFP）表达，最重要的是，它表现出HCC特异性复制，并且在非HCC肿瘤细胞或正常肝细胞中不复制。我们对从连续感染周期收集到的ACE-GFP-EIIAFP的启动子区域进行了测序，以检查该载体在其复制传播过程中的基因组稳定性，并发现该载体可以在基因组中保留杂种启动子至少六个感染周期。体外研究表明，分别表达酵母胞嘧啶脱氨酶和大肠杆菌嘌呤核苷磷酸化酶的ACE-CD-EIIAFP和ACE-PNP-EIIAFP，在各自前药存在下，对HCC细胞具有很强的细胞毒性作用。在体内，ACE-CD-EIIAFP介导的自杀基因疗法有效地抑制了HCC肿瘤的生长，并且在肿瘤外组织中未观察到可检测到的RRV信号。这些结果表明，肿瘤特异性，自杀基因编码的RRV可能实现了逆转录病毒基因治疗癌症的希望。

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