Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
J Gene Med. 2010 Jul;12(7):586-95. doi: 10.1002/jgm.1471.
Adeno-oncolytic (Adon) viruses offer an effective cancer therapeutic tool with several advantages, including wide host cell permeability, high transduction efficiency, safety, tumor selectivity, non-invasiveness, high genetic modifiability and high level of expression of the integrated transgenes. Armed Adon viruses in which the therapeutic efficacy of virus is enhanced by their coupling with cytotoxic, anti-angiogenic or anti-vascular gene products have gained importance because they engage additional mechanisms for tumor cell killing. In the present study, we selected mortalin, a stress chaperone that is tightly involved in human carcinogenesis, constructed a mortalin-targeting Adon (mot-Adon) virus and examined its therapeutic potential both in vitro and in vivo.
Mortalin-targeting plasmid and viral vectors that harbored mortalin-specific small interfering RNA sequences were constructed. The therapeutic value of these vectors was investigated in vitro and in vivo by cell culture and nude mice tumor models.
We demonstrate that the mot-Adon virus has selective cytotoxicity for human cancer cells in vitro. Retrovirus-mediated overexpression of mortalin protected the cells against mot-Adon virus, confirming that mortalin silencing was the real cause of cancer cell death. Although mortalin overexpression enhanced malignant properties of cancer cells in breast xenograft models, mot-Adon virus elicited an enhanced anti-tumor effect. Immunohistochemical examination of the tumors showed that the mot-Adon virus caused enhanced apoptosis (mediated by reactivation of p53) and suppression of microvessel formation.
Mortalin is up-regulated in a large variety of tumors and hence mot-Adon virus is proposed as a candidate cancer therapeutic agent.
腺病毒溶瘤（Adon）病毒是一种有效的癌症治疗工具，具有多种优势，包括广泛的宿主细胞通透性、高转导效率、安全性、肿瘤选择性、非侵入性、高遗传可修饰性和整合转基因的高水平表达。武装 Adon 病毒通过与细胞毒性、抗血管生成或抗血管基因产物结合来增强其治疗效果，因为它们采用了额外的肿瘤细胞杀伤机制，因此变得越来越重要。在本研究中，我们选择了热休克蛋白 mortalin，它与人类癌症的发生密切相关，构建了靶向 mortalin 的 Adon（mot-Adon）病毒，并在体外和体内研究了其治疗潜力。
构建了靶向 mortalin 的质粒和病毒载体，这些载体携带 mortalin 特异性的小干扰 RNA 序列。通过细胞培养和裸鼠肿瘤模型研究了这些载体在体外和体内的治疗价值。
我们证明 mot-Adon 病毒在体外对人癌细胞具有选择性细胞毒性。逆转录病毒介导的 mortalin 过表达保护细胞免受 mot-Adon 病毒的侵害，证实 mortalin 沉默是癌细胞死亡的真正原因。尽管 mortalin 过表达增强了乳腺癌异种移植模型中癌细胞的恶性特性，但 mot-Adon 病毒产生了增强的抗肿瘤作用。对肿瘤的免疫组织化学检查表明，mot-Adon 病毒引起了增强的细胞凋亡（由 p53 的重新激活介导）和微血管形成的抑制。
mortalin 在多种肿瘤中上调，因此 mot-Adon 病毒被提议作为候选癌症治疗剂。
