Are hepatomas a good target for suicide gene therapy? An experimental study in rats using retroviral-mediated transfer of thymidine kinase gene.

Abstract

Suicide gene transfer into tumor cells has been proposed for the treatment of various tumors. The most common suicide gene is coded for the herpes simplex type I thymidine kinase (HSV1-TK), which converts nontoxic nucleoside analogs such as ganciclovir into toxic triphosphated compounds. This study evaluated the potential of this treatment for gene therapy of liver tumors. The sensitivity of different colon carcinoma and hepatoma cell lines to infection by recombinant retroviruses was evaluated. Next, HSV1-TK-expressing derivatives of these cells were generated to analyze their sensitivity to ganciclovir. Finally, these cells were used to generate experimental hepatomas in rats after injection under the liver capsule, and the efficacy and safety of a ganciclovir treatment on tumor growth and survival were evaluated. All the different cell lines analyzed were sensitive to retroviral-mediated gene transfer, although the susceptibility of individual cell lines to this transfer varied significantly. HSV1-TK derivatives were about 1000-fold more sensitive to the toxic effects of ganciclovir than parental cells. Tumors with HSV1-TK expressing MCA-RH8994 hepatoma cells were then generated. Intraperitoneal injection of 75 mg/kg ganciclovir twice daily for 5 days dramatically reduced the size of HSV1-TK-positive tumors compared with tumor size in untreated control rats (0.4 mm3 versus 65 mm3, p < 0.02). A long-term study demonstrated that this reduction of tumor volume was associated with a significant increase in survival (p < 0.01). Pathologic examination 26 days after the end of ganciclovir injections showed that complete tumor regression was observed in two of five rats. Most important, there was no toxicity associated with these tumors. In a clinical perspective the good tolerance to treatment and the significant clinical effect observed were encouraging. Gene transfer methods should be established to allow efficient targeting of the tumor cells in vivo.