Gene therapy of hepatocellular carcinoma and gastrointestinal tumors.

Primary liver cancer and liver metastases from gastrointestinal tumors lack effective therapy. Gene therapy is a promising therapeutic approach and is based on the introduction of genetic material into cells to generate a curative biological effect. Adenoviral vectors can very efficiently transduce a wide variety of malignant epithelial cells both in vitro and in vivo. A variety of gene therapy-based anticancer strategies have been effective in animal tumor models, including replacement of tumor suppressor genes, selective activation of prodrugs, genetic immunotherapy, and antiangiogenic actions. Enzymes used for genetic activation include viral thymidine kinase (tk), which may activate nucleoside analogs such as ganciclovir. We and others have demonstrated the efficacy of the tk/ganciclovir system in the treatment of hepatocellular carcinoma and metastatic colorectal cancer in experimental models. Also, this strategy can be safely applied to patients with liver tumors. Interleukin-12 (IL-12) is among the most potent cytokines in stimulating antitumor immunity. In models of primary and metastatic liver cancer we showed that intratumoral administration of recombinant adenovirus encoding IL-12 activates natural killer cells, induces specific antitumor immunity, and displays a powerful antiangiogenic effect, resulting in tumor regression. There is a synergistic effect with the gene transfer of the chemokine IP-10. Also, intratumoral injection of either dendritic cells transfected ex vivo with recombinant adenovirus encoding IL-12 (Ad.IL-12) or an adenovirus coding for the CD40 ligand have shown an intense antitumor effect against experimental colorectal cancer. In summary, a variety of gene therapy strategies have been effective against animal models of gastrointestinal tumors. Clinical trials should determine whether human patients can be treated safely and effectively by such strategies.