Adenoviral Delivery of Recombinant DNA into Transgenic Mice Bearing Hepatocellular Carcinomas

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Abstract
To evaluate the applicability of recombinant adenoviral vectors in gene transfer to liver cancers, we infused the recombinant adenoviruses AD5CMV-LacZ and Ad5CMV-p53 through the portal veins into two lines of transgenic mice, one bearing the SV40 T antigen and the other the human hepatitis B viral envelope protein. These transgenic animals develop hepatocellular carcinomas (HCC) with predictable pathological manifestations. The levels of expression of the transgenes were dependent upon the viral doses. In all cases, high levels of expression were detected within 2 or 3 days after infusion, but were drastically reduced 7 days after infusion. Significant toxicities were found in the infused animals: >80% of them died within 7 days after infusion with 1010 pfu, and transgenic animals bearing HCC apparently were more sensitive to viral toxicity. Although a lower dose (109 pfu/animal) produced less toxicity, the levels of expression were substantially reduced (only about 10% of that in animals infused with 1010 pfu). When Ad5CMV-p53 was infused into animals with nodular hyperplastic stage, the expression of the reporter gene seemed to distribute preferentially at the peripheries of the tumor nodules, and low levels of transgene expression were seen inside the nodules. In tumors in which necrotic lesions were evident, p53 was also expressed at the perpheries of the lesions. These distribution patterns were seen in both tumor models. There was no apparent suppression of tumor growth in the Ad5CMV-p53-infused animals. Our results suggest that alternative methods for gene therapy for HCC need to be explored. This study demonstrated that although recombinant adenovirus can be used to transfer genes into hepatocellular car-cinomas developed in transgenic mice with high levels of expression, the cytotoxicity of recombinant adenoviruses, the transient nature of transgene expression, and the nonuniform distribution of the expressed gene in tumor-bearing livers suggest that alternative methods of gene therapy for primary liver cancers need to be explored.