Gerolami Rene, Uch Rathviro, Faivre Jamila, Garcia Stephane, Hardwigsen Jean, Cardoso Jorge, Mathieu Sylvie, Bagnis Claude, Brechot Christian, Mannoni Patrice
INSERM UR559, Faculté de Médecine de La Timone, Marseille, France.
J Hepatol. 2004 Feb;40(2):291-7. doi: 10.1016/j.jhep.2003.10.019.
BACKGROUND/AIMS: Gene therapy is a promising approach for treatment of hepatocellular carcinoma (HCC). However, transduction of non-tumoral hepatocytes may lead to severe hepatitis when using suicide gene therapy approaches. The aim of our study was to evaluate the gene transfer efficiency into HCC cells and normal hepatocytes using human immunodeficiency virus (HIV)-derived lentiviral vectors in vitro and in vivo.
Lentiviral vectors encoding for the LacZ gene or the fusion gene HSV-Tk/GFP were tested in vitro in human HCC cells and human hepatocytes in primary culture and in vivo in a chemically induced rat model of HCC.
We show that HIV-1-derived lentiviral vectors are efficient in transducing HCC cells in vitro and in vivo. No significant transduction of non-tumorous hepatocytes was observed in vivo whatever the route of administration used. Measurement of tumor growth following direct intratumoral injection of a lentiviral vector containing the HSV-Tk gene and GCV treatment showed a strong antitumoral efficacy in the absence of normal liver toxicity.
These observations suggest that lentiviral vectors allow an antitumoral effect with low liver toxicity when using suicide gene therapy approach and could be efficient tools for HCC gene therapy.
背景/目的：基因治疗是肝细胞癌（HCC）治疗的一种有前景的方法。然而，在使用自杀基因治疗方法时，非肿瘤性肝细胞的转导可能导致严重肝炎。我们研究的目的是在体外和体内使用人免疫缺陷病毒（HIV）衍生的慢病毒载体评估基因导入HCC细胞和正常肝细胞的效率。
编码LacZ基因或融合基因HSV-Tk/GFP的慢病毒载体在体外原代培养的人HCC细胞和人肝细胞中以及在化学诱导的大鼠HCC模型体内进行测试。
我们表明HIV-1衍生的慢病毒载体在体外和体内转导HCC细胞均有效。无论采用何种给药途径，在体内均未观察到非肿瘤性肝细胞的显著转导。在直接瘤内注射含HSV-Tk基因的慢病毒载体并进行GCV治疗后测量肿瘤生长，结果显示在无正常肝毒性的情况下具有强大的抗肿瘤功效。
这些观察结果表明，当使用自杀基因治疗方法时，慢病毒载体可产生低肝毒性的抗肿瘤作用，并且可能是HCC基因治疗的有效工具。
