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

用具有复制能力的HSV 1型（HSV-1）突变体治疗溶瘤性单纯疱疹病毒（RSV）是治疗口腔癌的一种很有前途的方法，因为癌细胞内HSV-1的复制可以导致它们的破坏。对于口腔肿瘤的治疗，确定口腔环境因素如何影响HSV-1载体的复制是至关重要的。我们检查了钙离子载体、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，而没有改变病毒的产生。此外，H2O2升高细胞内钙（[Ca2+]i）水平，进而使细胞外HSV-1升高，提示[Ca2+]i在HSV-1载体的释放中起重要作用。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。一种极性化合物六亚甲基双卡他胺（HMBA）可增强γ - 34.5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SCC的溶瘤作用。恶性纤维组织细胞瘤（MFH）是成人最常见的软组织肉瘤。近70%的原代人MFH在不同水平上表达钙钙蛋白，在口腔MPH细胞中检测了钙钙蛋白启动子衍生ICP4表达的HSV-1突变体d12 CALP的复制，d12 CALP在表达钙钙蛋白的口腔MFH中证实了细胞病变作用。将MFH裸鼠异种移植物注射d12 CALP后，观察到肿瘤生长明显减少。此外，静脉注射该载体可导致d12 CALP在肺转移灶中的复制。该载体可用于MFH远处转移的治疗。

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.