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增强感染性、条件复制型腺病毒用于 COX-2 表达的去势抵抗性前列腺癌。

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

机构信息

Division of Human Gene Therapy, Department of Surgery, Medicine and Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

出版信息

Viruses. 2023 Mar 31;15(4):901. doi: 10.3390/v15040901.

DOI:10.3390/v15040901

PMID:37112881

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10144787/

Abstract

BACKGROUND

The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues.

METHODS

The properties of the COX-2 promoter and the effect of fiber modification were tested in two CRPC cell lines (Du-145 and PC3). Fiber-modified COX-2 CRAds were tested in vitro for cytocidal effect as well as in vivo for antitumor effect with subcutaneous CRPC xenografts.

RESULTS

In both CRPC cell lines, the COX-2 promoter showed high activity, and Ad5/Ad3 fiber modification significantly enhanced adenoviral infectivity. COX-2 CRAds showed a potent cytocidal effect in CRPC cells with remarkable augmentation by fiber modification. In vivo, COX-2 CRAds showed an antitumor effect in Du-145 while only Ad5/Ad3 CRAd showed the strongest antitumor effect in PC3.

CONCLUSION

COX-2 promoter-based, infectivity-enhanced CRAds showed a potent antitumor effect in CRPC/NEPC cells.

摘要

背景

为去势抵抗性前列腺癌（CRPC），特别是神经内分泌前列腺癌（NEPC）开发条件复制型腺病毒（CRAd）存在两个主要障碍：控制元件的选择和较差的感染性。我们应用基于纤维修饰的感染性增强和非雄激素依赖性启动子（环氧化酶-2，COX-2）来克服这些问题。

方法

在两种 CRPC 细胞系（Du-145 和 PC3）中测试 COX-2 启动子的性质和纤维修饰的效果。纤维修饰的 COX-2 CRAd 在体外进行细胞杀伤作用测试，在皮下 CRPC 异种移植模型中进行体内抗肿瘤作用测试。

结果

在两种 CRPC 细胞系中，COX-2 启动子均显示出高活性，Ad5/Ad3 纤维修饰显著增强了腺病毒的感染性。COX-2 CRAd 在 CRPC 细胞中具有很强的细胞杀伤作用，纤维修饰显著增强了其效果。在体内，COX-2 CRAd 在 Du-145 中显示出抗肿瘤作用，而只有 Ad5/Ad3 CRAd 在 PC3 中显示出最强的抗肿瘤作用。