Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir therapy of hepatocellular carcinoma: The woodchuck animal model
R. Bilbao et al., Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir therapy of hepatocellular carcinoma: The woodchuck animal model, CANC GENE T, 7(5), 2000, pp. 657-662
Gene therapy for hepatocellular carcinoma (HCC) has shown some promise, but
its evaluation requires relevant experimental models. With this aim, we pr
esent an evaluation of the interest of using the woodchuck model of HCC to
assess in vivo gene transfer efficiency. We tested the transduction efficac
y of the adenoviral vectors directing lacZ gene product expression under th
e control of the cytomegalovirus and alpha-fetoprotein (AFP) regulatory seq
uences. We have also investigated whether an adenoviral cytomegalovirus-thy
midine kinase (Tk) vector might induce an antitumoral effect in this model.
Our results demonstrate that with direct intratumoral and intrahepatic art
erial injections, transduction of a significant proportion of tumor cells o
ccurred even in large HCC nodules. Furthermore, due to intra-arterial anast
omoses, direct intratumoral injection led to transduction of some noninject
ed HCC nodules. Moreover, direct intratumoral injection of a herpes simplex
virus-1 Tk-encoding vector induced, on ganciclovir administration, a signi
ficant antitumoral effect in the two animals evaluated. However, in one ani
mal, massive hepatic failure occurred due to Tk expression in nontumor cell
s. 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. Ho
wever, we showed that, in vivo, lacZ expression as driven by the AFP promot
er was extremely low, thus emphasizing some potential pitfalls when using t
his approach. Altogether, our data stress the need to test gene therapy-bas
ed strategies in such in vivo animal models of HCC and evaluate gene transd
uction, expression, and biological activity, as well as its potential toxic
ity.