Tissue-Specific Expression of Herpes Simplex Virus Thymidine Kinase Gene Delivered by Adeno-Associated Virus Inhibits the Growth of Human Hepatocellular Carcinoma in Athymic Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-12, Vol.94 (25), p.13891-13896
• Main Authors: Su, Hua, Lu, Ronghua, Chang, Judy C., Kan, Yuet Wai
• Format: Article
• Language: English
• Subjects: Albumins; Animals; Base Sequence; Biological Sciences; Cancer; Cell lines; Cells; Dependovirus - genetics; DNA Primers - genetics; Enzymes; Epithelial cells; Gene Expression; Genes; Genes, Viral; Genetic Therapy; Genetic Vectors; Hepatocellular carcinoma; Herpes viruses; Humans; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - therapy; Medical research; Mice; Mice, Nude; Neoplasm Transplantation; Polymerase Chain Reaction; Recombination, Genetic; Reverse transcriptase polymerase chain reaction; Rodents; Simplexvirus - enzymology; Simplexvirus - genetics; Thymidine Kinase - genetics; Transduction, Genetic; Transplantation, Heterologous; Tumor cell line; Tumors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.25.13891

About 70% of hepatocellular carcinomas are known to express α -fetoprotein, which is normally expressed in fetal but not in adult livers. To induce herpes simplex virus-thymidine kinase expression in these cancer cells, we constructed an adeno-associated viral vector containing the HSV-TK gene under the control of the α -fetoprotein enhancer and albumin promoter. We previously demonstrated in vitro that although this vector can transduce a variety of human cells, only transduced AFP and albumin-expressing hepatocellular carcinoma cell lines were sensitive to killing by ganciclovir (GCV). In the present study, we explored the effect of this vector on hepatocellular carcinoma cells in vivo. Subcutaneous tumors generated in nude mice by implanting hepatocellular carcinoma cells previously transduced with this vector shrank dramatically after treatment with GCV. Bystander effect was also observed on the tumors generated by mixing transduced and untransduced cells. To test whether the tumor cells can be transduced by the virus in vivo, we injected the recombinant adeno-associated virus into tumors generated by untransduced hepatocarcinoma cell line. Tumor growth were retarded after treatment with GCV. These experiments demonstrate the feasibility of in vivo transduction of tumor cell with rAAV.