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Gene therapy for oral squamous cell carcinoma with herpes simplex virus vector

单纯疱疹病毒载体治疗口腔鳞状细胞癌的基因治疗

基本信息

批准号：
13470432
负责人：
YURA Yoshiaki
金额：
$ 7.42万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470432/
关键词：
gene therapy oral cancer herpes simplex virus mutant virus HMBA calponin malignant histiocytoma 複製可能型組換えウイルス三叉神経神経再建細胞融合

项目摘要

Oncolytic herpes simplex virus (RSV) therapy with replication-competent HSV type 1(HSV-1) mutant is a promising approach for the treatment of oral cancer, because replication of HSV-1 within cancer cells can result in their destruction. For the treatment of cancer in the oral cavity, it is essential to determine how oral environmental factors could affect the replication of HSV-1 vector. We examined the effect of a calcium ionophore, ionomycin, and oxygen radicals and found that ionomycin increased entracellular virus, whereas it did not change the virus production. Furthermore, H2O2 elevated the level of intracellular calcium ([Ca2+]i) and then increased the extracellular HSV-1, suggesting that [Ca2+]i plays an important role in the release of HSV-1 vector. To eradicate solid tumor, HSV-1 vector must spread from inoculated site to neighboring tumor cells. A polar compound, hexamethylene bisacatamide (HMBA) was found to enhance the replication of γ34.5 mutant R849 in human oral squamous cell carcinoma (SCC) cells. This indicated that HMBA can potentiate the oncolytic effect of R849 on human oral SCC. Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in adult. Nearly 70% of primary human MFH express calponin at various levels, The replication of a HSV-1 mutant d12 CALP in which calponin promoter derives expression of ICP4 was examined in oral MPH cells, Cytopathic effect of d12 CALP was demonstrated in oral MFH that expressed calponin. When nude mice xenografts of MFH were injected with the d12 CALP, a significant reduction of the tumor growth was observed. Furthermore, intravenous administration of the vector resulted in the replication of d12 CALP in lung metastatic lesions. This vector could be usedd for the treatment of distant metastasis of MFH.

用具有复制能力的HSV-1型（HSV-1）突变体的溶瘤单纯疱疹病毒（RSV）治疗是用于治疗口腔癌的有希望的方法，因为HSV-1在癌细胞内的复制可导致其破坏。为了治疗口腔癌，必须确定口腔环境因素如何影响HSV-1载体的复制。我们研究了钙离子载体、离子霉素和氧自由基的作用，发现离子霉素增加了细胞内病毒，而它没有改变病毒的产生。H_2O_2可使细胞内钙离子（[Ca ~（2+）]i）水平升高，进而使细胞外HSV-1浓度升高，提示[Ca ~（2+）]i在HSV-1载体释放中起重要作用。为了根除实体瘤，HSV-1载体必须从接种部位扩散到邻近的肿瘤细胞。发现极性化合物双乙酰胺（HMBA）可增强γ34.5突变体R849在人口腔鳞状细胞癌（SCC）细胞中的复制。这表明HMBA可以增强R849对人口腔鳞癌的溶瘤作用。恶性纤维组织细胞瘤是成人最常见的软组织肉瘤。近70%的原代人MFH表达不同水平的calponin，检测了HSV-1突变型d12卡尔普在口腔MPH细胞中的复制，d12卡尔普在表达calponin的口腔MFH中表现出细胞病变。当用d12卡尔普注射MFH的裸鼠异种移植物时，观察到肿瘤生长的显著减少。此外，静脉内施用载体导致d12卡尔普在肺转移病灶中复制。该载体可用于MFH远处转移的治疗。