Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model.
Gene therapy for hepatocellular carcinoma (HCC) has shown some promise, but its evaluation requires relevant experimental models. With this aim, we present an evaluation of the interest of using the woodchuck model of HCC to assess in vivo gene transfer efficiency. We tested the transduction efficacy of the adenoviral vectors directing lacZ gene product expression under the control of the cytomegalovirus and alpha-fetoprotein (AFP) regulatory sequences. We have also investigated whether an adenoviral cytomegalovirus-thymidine kinase (Tk) vector might induce an antitumoral effect in this model. Our results demonstrate that with direct intratumoral and intrahepatic arterial injections, transduction of a significant proportion of tumor cells occurred even in large HCC nodules. Furthermore, due to intra-arterial anastomoses, direct intratumoral injection led to transduction of some noninjected HCC nodules. Moreover, direct intratumoral injection of a herpes simplex virus-1 Tk-encoding vector induced, on ganciclovir administration, a significant antitumoral effect in the two animals evaluated. However, in one animal, massive hepatic failure occurred due to Tk expression in nontumor cells. These results emphasize the need to target the expression of the Tk gene to tumor cells using a hepatoma-specific promoter such as AFP promoter. However, we showed that, in vivo, lacZ expression as driven by the AFP promoter was extremely low, thus emphasizing some potential pitfalls when using this approach. Altogether, our data stress the need to test gene therapy-based strategies in such in vivo animal models of HCC and evaluate gene transduction, expression, and biological activity, as well as its potential toxicity.
Bilbao
R
R
Department of Internal Medicine, University of Navarra, Pamplona, Spain.
Gérolami
R
R
Bralet
M P
MP
Qian
C
C
Tran
P L
PL
Tennant
B
B
Prieto
J
J
Bréchot
C
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D003587:Cytomegalovirus / Q000201:enzymology; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000627:therapeutic use* / Q000633:toxicity; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D008392:Marmota; D009336:Necrosis; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000096:biosynthesis
D000998:Antiviral Agents; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir