HERPES SIMPLEX VIRUS IN THE TREATMENT OF ORAL CANCER

单纯疱疹病毒治疗口腔癌

• 批准号: 6634661
• 负责人: EDWARD J. SHILLITOE
• 金额: $ 25.72万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634661
• 关键词: athymic mouse; cytokine; cytotoxicity; disease /disorder model; ganciclovir; gene expression; gene therapy; genetic promoter element; genetic strain; herpes simplex virus 1; immune tolerance /unresponsiveness; molecular cloning; mutant; neoplasm /cancer therapy; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; oral pharyngeal neoplasm; polymerase chain reaction; tissue /cell culture; transfection /expression vector; virus genetics; virus replication

We will develop new strains of Herpes simplex virus type-1 (HSV- 1) for use in the treatment of oral cancer. HSV- 1 has potential as a therapeutic tool for oral cancer since it infects oral epithelium as its natural host tissue, is highly cytotoxic, and spreads rapidly from one cell to another. The only disadvantage of HSV-1 is that it can spread to the nervous system, causing paralysis and death. To prevent this, we will develop a new strain of the virus whose replication is limited to oral cancer cells. This will be done by removing a promoter that controls expression of an essential viral gene, and replacing it with a promoter that is active in oral cancer cells but not in nervous- system cells. We will increase the anti-tumor effect of the virus by adding a gene for a cytokine. This will increase the local immune response to the infected tumor. We will then make the anti-tumor effect even stronger by exploiting the anti-tumor bystander effect that occurs when ganciclovir is activated by HSV-1. We expect that the triple combination of a tumor- restricted virus, enhanced local immune response, and anti-tumor bystander effect will be more effective in treatment of an experimental model of oral cancer than other treatments, and could lead to human trials in the future.

我们将开发新的1型单纯疱疹病毒（HSV- 1）毒株用于口腔癌的治疗。HSV- 1有潜力作为口腔癌的治疗工具，因为它感染作为其天然宿主组织的口腔上皮，具有高度的细胞毒性，并且在细胞间迅速传播。HSV-1唯一的缺点是它可以扩散到神经系统，导致瘫痪和死亡。为了防止这种情况，我们将开发一种新的病毒株，其复制仅限于口腔癌细胞。这将通过去除控制基本病毒基因表达的启动子，并用在口腔癌细胞中有活性但在神经系统细胞中没有活性的启动子取代它来实现。我们将通过添加细胞因子基因来增强病毒的抗肿瘤作用。这将增加局部对感染肿瘤的免疫反应。然后，我们将利用更昔洛韦被HSV-1激活时产生的抗肿瘤旁观者效应，使其抗肿瘤效果更强。我们预计，肿瘤限制病毒、增强局部免疫反应和抗肿瘤旁观者效应的三重组合在口腔癌实验模型的治疗中将比其他治疗方法更有效，并可能在未来进行人体试验。