Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
Cancer Lett. 2011 Jul 1;306(1):92-8. doi: 10.1016/j.canlet.2011.02.036. Epub 2011 Apr 8.
Gene therapy using an adenoviral vector expressing tumor necrosis factor-alpha (TNF-α) is a new therapeutic approach for pancreatic cancer. However, the efficacy of TNF-α is limited, because it activates nuclear factor-κB (NF-κB). We investigated the combined use of AxCAhTNF-α, adenoviral vector-expressing human TNF-α, and nafamostat mesilate, a serine-protease inhibitor, a NF-κB inhibitor, using pancreatic cancer in mice. In vitro, nafamostat mesilate inhibited TNF-α-induced NF-κB activation and enhanced TNF-α-induced apoptosis in human cancer cell line (MIAPaCa-2). In vivo, we assessed combination treatment of AxCAhTNF-α and nafamostat mesilate using xenograft models in nude mice by subcutaneous injection of MIAPaCa-2. When the implanted tumor size reached 8.0mm, TNF-α group (n=12), was injected AxCAhTNF-α intra-tumorally once a week, while combination group (n=12), was injected AxCAhTNF-α intra-tumorally once a week and nafamostat mesilate intraperitoneally thrice a week. In combination group, tumor growth was significantly slower, and the number of apoptosis cells was significantly greater than those in AxCAhTNF-α group (p<0.05). In conclusion, adenovirus vector-mediated TNF-α gene therapy combined with nafamostat mesilate was effective for pancreatic cancer in mice.
利用腺病毒载体表达肿瘤坏死因子-α（TNF-α）的基因治疗是胰腺癌的一种新的治疗方法。然而，TNF-α 的疗效有限，因为它会激活核因子-κB（NF-κB）。我们使用小鼠胰腺癌研究了 AxCAhTNF-α、表达人 TNF-α 的腺病毒载体和丝氨酸蛋白酶抑制剂纳曲酶联合应用的效果，纳曲酶是一种 NF-κB 抑制剂。在体外，纳曲酶抑制 TNF-α 诱导的 NF-κB 激活并增强人癌细胞系（MIAPaCa-2）中 TNF-α 诱导的细胞凋亡。在体内，我们通过在裸鼠中皮下注射 MIAPaCa-2，使用异种移植模型评估 AxCAhTNF-α 和纳曲酶联合治疗的效果。当植入的肿瘤大小达到 8.0mm 时，TNF-α 组（n=12）每周一次瘤内注射 AxCAhTNF-α，而联合组（n=12）每周一次瘤内注射 AxCAhTNF-α，每周三次腹腔内注射纳曲酶。在联合组中，肿瘤生长明显减慢，凋亡细胞数量明显多于 AxCAhTNF-α 组（p<0.05）。总之，腺病毒载体介导的 TNF-α 基因治疗联合纳曲酶对小鼠胰腺癌有效。
