Naito S, Obayashi S, Sumi T, Iwai S, Nakazawa M, Ikuta K, Yura Y
Department of Oral and Maxillofacial Surgery II, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.
Cancer Gene Ther. 2006 Aug;13(8):780-91. doi: 10.1038/sj.cgt.7700957. Epub 2006 Apr 28.
Current oncolytic viruses exert only limited antitumor activity on their own. There is a need to increase their oncolytic capability. We evaluated the effect of a differentiating reagent, hexamethylene bisacetamide (HMBA), on the antitumor activity of a gamma(1)34.5-deficient herpes simplex virus type 1 (HSV-1) R849 for human oral squamous cell carcinoma (SCC) cells. Hexamethylene bisacetamide increased the viral yield, especially at a low input multiplicity of infection (MOI), and the transcription of immediate early genes of HSV-1. Hexamethylene bisacetamide treatment promoted the cytopathic effect of R849 and increased the proportion of dead cells. Hexamethylene bisacetamide produced more apoptotic cells in R849-infected cells as compared with parental HSV-1(F)-infected cells. The growth of oral SCC xenografts in nude mice was markedly suppressed by treatment with R849 in combination with HMBA, and the survival of the co-treated animals was significantly prolonged as compared with that of animals treated with R849 only. Herpes simplex virus type 1 mRNA was expressed in tumors and trigeminal neurons, but not in brain, lung, liver, and kidney. These results indicate that HMBA enhances the antitumor activity of R849 through the expression of immediate early genes without increasing its toxicity. Hexamethylene bisacetamide can be used as an enhancing agent for oncolytic therapy with HSV-1 mutants.
目前的溶瘤病毒自身仅发挥有限的抗肿瘤活性。有必要提高它们的溶瘤能力。我们评估了一种分化试剂，六亚甲基双乙酰胺（HMBA），对γ(1)34.5缺陷型单纯疱疹病毒1型（HSV-1）R849针对人口腔鳞状细胞癌（SCC）细胞的抗肿瘤活性的影响。六亚甲基双乙酰胺提高了病毒产量，尤其是在低感染复数（MOI）时，并且提高了HSV-1即刻早期基因的转录。六亚甲基双乙酰胺处理促进了R849的细胞病变效应并增加了死亡细胞的比例。与亲本HSV-1(F)感染的细胞相比，六亚甲基双乙酰胺在R849感染的细胞中产生了更多的凋亡细胞。用R849联合HMBA处理可显著抑制裸鼠口腔SCC异种移植瘤的生长，并且与仅用R849处理的动物相比，联合处理动物的生存期显著延长。单纯疱疹病毒1型mRNA在肿瘤和三叉神经节神经元中表达，但在脑、肺、肝和肾中不表达。这些结果表明，HMBA通过即刻早期基因的表达增强了R849的抗肿瘤活性，而不增加其毒性。六亚甲基双乙酰胺可用作HSV-1突变体溶瘤治疗的增强剂。
