Department of Genetics, Hyogo College of Medicine, Nishinomiya, Japan.
Cancer Sci. 2013 Nov;104(11):1433-9. doi: 10.1111/cas.12267. Epub 2013 Sep 23.
Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma.
溶瘤病毒治疗法利用腺病毒在恶性间皮瘤中有治疗的潜力。然而，柯萨奇病毒/腺病毒受体（CAR）表达下调常常是一个关键的限速因素，它会阻碍腺病毒 5 型（Ad5）为基础的载体在许多癌症类型中的有效性。我们评估了 6 个人类恶性间皮瘤细胞系中的 CAR（Ad5 受体）和 CD46（腺病毒 35 型[Ad35]受体）的表达。在 MSTO-211H 和 NCI-H2052 细胞中观察到非常低的 CAR 表达，而其他细胞系则表现出强烈的表达。相比之下，CD46 在所有间皮瘤细胞系中都高度表达。在此基础上，我们在复制缺陷型腺病毒和肿瘤特异性中期因子启动子调控的溶瘤腺病毒中将 Ad5 的 CAR 结合序列替换为 Ad35 的 CD46 结合序列。通过这种纤维修饰，腺病毒在低 CAR 表达的 MSTO-211H 和 NCI-H2052 细胞中的感染性、病毒子代产生和体外细胞杀伤作用显著增强，在高 CAR 表达的间皮瘤细胞系中也产生了相似甚至更高的水平。在 MSTO-211H 异种移植模型中，纤维修饰的溶瘤腺病毒与等效的 Ad5 为基础的载体相比，显著增强了抗肿瘤效果。我们的数据表明，在中期因子启动子调控的溶瘤 Ad5 载体中，Ad35 纤维修饰改变了结合嗜性，赋予了转导靶向性，从而更有效地治疗恶性间皮瘤。
