PDF(Pubmed)
Abstract：
Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF\'s selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF\'s impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF\'s potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.
摘要：
溶瘤病毒疗法,使用水泡性口炎病毒（VSVΔ51）和单纯疱疹病毒-1（HSV-1）等病毒选择性攻击癌细胞，面临挑战，如干扰素（IFN）反应介导的细胞抗性。富马酸二甲酯（DMF）用于治疗多发性硬化症和牛皮癣，并因其抗癌特性而得到认可，并已显示可增强VSVΔ51和HSV-1溶瘤活性。富马酸泰匹胺（TPF）是目前正在进行临床试验的DMF类似物，用于治疗中度至重度斑块状牛皮癣。这项研究的目的是评估TPF增强溶瘤病毒有效性的潜力。体外，TPF治疗使786-0癌细胞更容易感染VSVΔ51，导致病毒复制增加。在增加病毒感染和增加这些抗性癌细胞和其他测试的癌细胞系的杀伤方面，它优于DMF。离体研究表明TPF选择性增强癌细胞中的溶瘤病毒感染而不影响健康组织。在胰腺和卵巢肿瘤样品中的有效性显著高。我们的研究进一步表明，TPF可以通过类似于DMF的机制下调IFN途径，使耐药癌细胞更容易受到病毒感染。此外，评估了TPF对基因治疗的影响，揭示了其增强慢病毒等载体转导效率的能力，腺病毒5型和腺相关病毒2型跨各种细胞系。该数据强调了TPF不仅在溶瘤病毒治疗中而且在基因治疗的更广泛的应用中的潜在作用。总的来说，这些发现将TPF定位为溶瘤病毒疗法中的有前途的药物，保证进一步探索其治疗潜力。
