Department of Ophthalmology, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Beijing, China.
Brain Tumor Research Center, Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing, China.
Cancer Lett. 2020 Dec 28;495:123-134. doi: 10.1016/j.canlet.2020.09.013. Epub 2020 Sep 15.
Uveal melanoma (UM) is the most common intraocular tumor in adults and has a high incidence of metastases. Possible treatments remain limited in UM with enucleation and radiation, leading to poor prognosis in this chemo-resistant carcinoma. Thus, urging demand for novel treatment is needed. We examined the antitumor efficacy of a new recombinant oncolytic herpes simplex virus type 1 (oHSV-1) armed with E.coli cytosine deaminase (CD). We determined the efficacy of the oncolytic virus in UM cell lines. In vivo experiments showed that oHSV-CD/5-fluorocytosine (5-FC) treatment reduce tumor volume and prolonged survival. We further demonstrated the molecular mechanisms of oHSV-CD/5-FC treatment. The oncolytic virus down-regulated IL-6 expression and thereby reversed the epithelial-mesenchymal transition (EMT) phenotype. Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) metabolism, was also down-regulated. Therefore, the efficacy of oHSV-CD/5-FC was synergistically enhanced by DPD down-regulation and EMT inhibition. This study provides solid evidence for the antitumor efficacy of oHSV-CD/5-FC treatment in vitro and in vivo. The molecular mechanisms of this treatment may bring a new therapeutic approach for future treatment of UM.
葡萄膜黑色素瘤（UM）是成年人中最常见的眼内肿瘤，且具有较高的转移率。在 UM 中，除了眼球摘除和放疗外，可能的治疗方法仍然有限，这导致这种对化疗有抗性的癌预后较差。因此，迫切需要新的治疗方法。我们研究了一种新的携带大肠杆菌胞嘧啶脱氨酶（CD）的重组单纯疱疹病毒 1 溶瘤病毒（oHSV-1）的抗肿瘤功效。我们确定了溶瘤病毒在 UM 细胞系中的疗效。体内实验表明，oHSV-CD/5-氟胞嘧啶（5-FC）治疗可减少肿瘤体积并延长生存期。我们进一步证明了 oHSV-CD/5-FC 治疗的分子机制。溶瘤病毒下调了 IL-6 的表达，从而逆转了上皮-间充质转化（EMT）表型。二氢嘧啶脱氢酶（DPD），5-氟尿嘧啶（5-FU）代谢中的限速酶，也被下调。因此，DPD 下调和 EMT 抑制协同增强了 oHSV-CD/5-FC 的疗效。这项研究为 oHSV-CD/5-FC 在体外和体内的抗肿瘤功效提供了确凿的证据。这种治疗的分子机制可能为未来 UM 的治疗带来新的治疗方法。
