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首页> 外文期刊>Journal of Hepatology: The Journal of the European Association for the Study of the Liver >Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma.
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Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma.

机译：在肝细胞癌的鼠模型中，自杀基因和白细胞介素12联合基因治疗比单独使用一个基因治疗更有效。

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BACKGROUND/AIMS: Gene therapy has emerged as a new form of treatment for unresectable hepatocellular carcinoma (HCC). We evaluate here the effect of IL-12 and the suicide gene thymidine kinase as single agents and in combination to treat experimental liver cancer. METHODS: Recombinant adenoviruses expressing mouse interleukin-12 (AdCMVIL-12) or thymidine kinase of herpes simplex virus (AdCMVtk) or lacZ reporter gene (AdCMVlacZ) were constructed. The efficacy of the treatment was evaluated in a murine HCC model based on subcutaneous implantation of liver tumor cells (BNL). RESULTS: Transduction of BNL cells after in vitro infection with AdCMVlacZ was very low at multiplicity of infection (moi) of 100, whereas 10-15% of cells were transduced when using moi 1,000. Similarly, production of IL-12 was detectable only in BNL cells infected with AdCMVIL-12 at moi 1,000. In vitro infection of BNL cells with AdCMVIL-12 at moi 100 did not abrogate tumorigenicity, whereas moi 1,000 resulted in inhibition of tumor growth in all mice as well as in abrogation of tumor formation in 3 out of 8 animals. In vivo studies showed that intratumor injection of AdCMVIL-12 induced a dose-dependent effect on tumor regression. However, none of the animals exhibited complete tumor elimination with this treatment. We observed that suppression of tumor growth was more intense in animals treated with the combination of AdCMVIL-12 plus AdCMVtk than in animals which received AdCMVtk or AdCMVIL-12 alone. The combined treatment resulted in a significant increase in animal survival, and 25% of treated animals were free of tumor for over 100 days without recurrence of the disease. CONCLUSIONS: Combination of AdCMVIL-12 and AdCMVtk is more efficient than either of the two vectors alone for the treatment of the murine model of HCC used in this study.
机译：背景/目的：基因治疗已成为不可切除肝细胞癌（HCC）的一种新型治疗方法。我们在这里评估IL-12和自杀基因胸苷激酶作为单一药物并联合治疗实验性肝癌的效果。方法：构建表达小鼠白细胞介素12（AdCMVIL-12）或单纯疱疹病毒（AdCMVtk）的胸苷激酶或lacZ报道基因（AdCMVlacZ）的重组腺病毒。在基于肝肿瘤细胞（BNL）皮下植入的小鼠HCC模型中评估了治疗效果。结果：在感染复数（moi）为100的情况下，用AdCMVlacZ体外感染后BNL细胞的转导非常低，而使用moi 1,000时可转导10-15％的细胞。同样，IL-12的产生仅在以Moi 1,000感染AdCMVIL-12的BNL细胞中可检测到。在Moi 100处用AdCMVIL-12体外感染BNL细胞并没有消除致瘤性，而moi 1,000导致所有小鼠中的肿瘤生长受到抑制，并且在8只动物中有3只导致肿瘤形成的消除。体内研究表明，肿瘤内注射AdCMVIL-12可对肿瘤消退产生剂量依赖性作用。然而，通过这种处理，没有动物显示出完全的肿瘤消除。我们观察到，与单独接受AdCMVtk或AdCMVIL-12的动物相比，用AdCMVIL-12加AdCMVtk联合治疗的动物对肿瘤生长的抑制作用更为强烈。联合治疗导致动物存活率显着增加，并且经过治疗的动物中有25％的动物在超过100天的时间内无肿瘤，且无疾病复发。结论：AdCMVIL-12和AdCMVtk的组合比单独使用两种载体治疗本研究中的HCC鼠模型更为有效。

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