Adenovirus-mediated gene transfer to orthotopic hepatocellular carcinomas in athymic nude mice

Abstract

Gene therapy may become an option for the treatment of malignant tumors such as hepatocellular carcinoma ( HCC ) , once safe and efficient vector systems have been established. Due to their stability in vivo, recombinant adenoviral vectors are promising vectors for gene delivery to HCC. To study the characteristics of gene delivery into HCCs by recombinant adenoviral vectors in vivo, we established an in situ HCC model in the livers of athymic nude mice by intrahepatic injection of human HCC cells. Recombinant adenovirus vectors expressing -galactosidase ( Ad2CMVgal ) were injected via the tail vein of mice bearing HCC or directly into intrahepatic tumors. Levels of -galactosidase expression in tumor tissue and surrounding normal liver were analyzed by histochemistry or for quantification by a chemiluminescence assay in tissue homogenates. Following tail vein injection, high levels of -galactosidase expression were found in the liver, but virtually no gene expression could be detected in the tumor tissue. In contrast, after direct injection of Ad2CMVgal into intrahepatic HCCs, high levels of -galactosidase expression were detected in the tumor tissue. However, single transduced hepatocytes scattered throughout the normal liver could also be identified. These results indicate that barriers such as the endothelial lining of the tumor vasculature impair the efficiency of adenoviral vectors for gene delivery into HCCs by intravenous administration, which can be overcome by direct injection into the tumor tissue. However, due to the observed transduction of disseminated hepatocytes following intratumoral administration, additional HCC -specific targeting to further enhance the safety of adenoviral vectors may be required. Cancer Gene Therapy ( 2001 ) 8, 573 -579

Oral adeno‐associated virus‐sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice†

“…However, it was not detectable in the subcutaneously transplanted tumor tissue via Western blot analysis or immunochemistry assay. This result supports the report by Yoon et al 26 that high levels of gene expression were observed in the liver, but virtually no gene expression could be detected in the tumor tissues of mice bearing orthotopic HCC administered with recombinant adenovirus vectors expressing ␤-galactosidase via the tail vein. This indicates that virus vectors could efficiently reach the liver via the blood supply after systemic administration (oral, intraperitoneal, or intravenous).…”

Specific systemic nonviral gene delivery to human hepatocellular carcinoma xenografts in SCID mice

“…Adenoviral vectors, despite their potential to transfect cells, have the clear drawback of predominantly transfecting hepatocytes upon intravenous application. [31][32][33] Although administration via the portal vein or the hepatic artery improves gene transfer into hepatic HCC nodules, high-expression levels are nevertheless found in the surrounding hepatocytes. 34,35 Strategies to tackle these problems include the use of tumor-specific promoters allowing transcriptional targeting of recombinant adenoviruses to HCC tumors.…”

Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter

“…However, the efficiency with which adenovirus tumor cells in the liver after systemic injection is substantially lower than the efficiency of direct intratumoral injection. 31 For this reason, in this study we began treating the liver tumors relatively early. Our results showed that treatment with Ad/TRAIL-F/RGD plus gemcitabine substantially suppressed the growth of pancreatic tumors in liver when the Ad/TRAIL-F/RGD was delivered systemically via the tail vein during an early treatment.…”