Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer
Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer
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DOI：
10.1038/sj.cgt.7700908
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发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Kaneko, S
中科院分区：
文献类型：
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作者：
Kagaya, T;Nakamoto, Y;Kaneko, S
使用单纯疱疹病毒胸苷激酶/更昔洛韦（HSV-tk/GCV）系统的自杀基因治疗是癌症基因治疗的良好表征的工具;然而，它尚未表现出足够的疗效来治愈恶性肿瘤患者。我们已经报道了腺病毒递送的单核细胞趋化蛋白（MCP）-1增强了HSV-tk/GCV系统在无胸腺裸鼠模型中的抗肿瘤作用。目前的研究，使用免疫活性小鼠模型的结肠癌，旨在评估MCP-1基因递送与这种自杀基因治疗系统结合的抗肿瘤作用。用表达HSV-tk基因和MCP-1、CD 80和LacZ基因的重组腺病毒（rAds）直接转导皮下肿瘤病灶，然后给予GCV。HSV-tk和MCP-1基因的联合转染可明显抑制肿瘤的生长，这与单核/巨噬细胞的募集、Th 1细胞因子基因的表达和脾细胞的细胞毒活性密切相关。此外，其抗肿瘤效果比HSV-tk和CD 80基因的组合获得的效果更有效。这些结果表明MCP-1在结肠癌自杀基因治疗的背景下通过协调先天性和获得性免疫应答的免疫调节作用。
Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a well-characterized tool for cancer gene therapy; however, it does not yet exhibit sufficient efficacy to cure patients of malignancies. We have reported that adenovirally delivered monocyte chemoattractant protein (MCP)-1 augmented the antitumor effects of the HSV-tk/GCV system in an athymic nude mouse model. The current study, which uses an immunocompetent mouse model of colon cancer, was designed to evaluate the antitumor effects of MCP-1 gene delivery in conjunction with this suicide gene therapy system. Subcutaneous tumor foci were directly transduced with both recombinant adenoviruses (rAds) expressing an HSV-tk gene and either of the MCP-1, CD80 and LacZ genes, followed by GCV administration. The growth of tumors was markedly suppressed by codelivery of HSV-tk and MCP-1 genes, which was exclusively associated with the recruitment of monocytes/macrophages, T helper 1 (Th1) cytokine gene expression and cytotoxic activity of the splenocytes. Furthermore, the antitumor effects were more efficient than that obtained by the combination of HSV-tk and CD80 genes. These results suggest an immunomodulatory effect of MCP-1 in the context of suicide gene therapy of colon cancer via orchestration of innate and acquired immune responses.