Herpes simplex virus thymidine kinase-mediated suicide gene therapy for hepatocellular carcinoma using HIV-1-derived lentiviral vectors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Gerolami
Rene
R
INSERM UR559, Faculté de Médecine de La Timone, Marseille, France. rene.gerolami@ap-hm.fr
Uch
Rathviro
R
Faivre
Jamila
J
Garcia
Stephane
S
Hardwigsen
Jean
J
Cardoso
Jorge
J
Mathieu
Sylvie
S
Bagnis
Claude
C
Brechot
Christian
C
Mannoni
Patrice
P
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007763:Lac Operon; D016086:Lentivirus / Q000235:genetics*; D008113:Liver Neoplasms / Q000628:therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic
D013937:Thymidine Kinase