Oncolysis of Multifocal Hepatocellular Carcinoma in the Rat Liver by Hepatic Artery Infusion of Vesicular Stomatitis Virus

• Published in: Molecular therapy Vol. 9; no. 3; pp. 368 - 376
• Main Authors: Shinozaki, Katsunori, Ebert, Oliver, Kournioti, Chryssanthi, Tai, Yun-Sheng, Woo, Savio L.C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2004; Elsevier Limited
• Subjects: Animals; beta-Galactosidase - genetics; cancer gene therapy; Cancer therapies; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cytokines - biosynthesis; Drug dosages; Galactosides - metabolism; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Hepatic Artery - metabolism; Hepatitis C; Humans; Immunohistochemistry; Indoles - metabolism; Inflammation; Infusions, Intra-Arterial; Kinetics; Liver - metabolism; Liver cancer; Liver Neoplasms - therapy; Male; Medical prognosis; Medicine; multifocal hepatocellular carcinoma; oncolytic virus; Rats; Time Factors; Veins & arteries; Vesicular stomatitis Indiana virus - genetics; Vesicular stomatitis Indiana virus - metabolism; vesicular stomatitis virus; Viruses; New York; United States > US; cancer gene therapy; multifocal hepatocellular carcinoma; oncolytic virus; vesicular stomatitis virus
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2003.12.004

Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis and few effective treatments, as well as ever-increasing frequencies in the Western world. Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to significantly attenuated antiviral responses in many tumor cells. The aim of this study was to evaluate the potential of VSV, administered via the hepatic artery, as an effective and safe therapeutic agent for treating “multifocal” HCC in the rat liver. Recombinant VSV vector expressing β-galactosidase (rVSV-β-gal) was generated by reverse genetics and infused into the hepatic artery of Buffalo rats bearing orthotopically implanted multifocal HCC. Access by the virus to multifocal HCC lesions in the liver, as well as the kinetic profiles of intratumoral viral replication and spread, was established by X-gal staining of liver and tumor sections. Plaque assays were also performed to determine the infectious viral yields in tumor and normal liver tissues. Pharmacotoxicology studies, including serum chemistries and proinflammatory cytokine production, as well as organ histopathology, were performed. Buffer- or vector-treated tumor-bearing rats were followed for survival and the results were analyzed by the Kaplan–Meier method and the log-rank test. Hepatic arterial infusion of rVSV-β-gal at the maximum tolerated dose in tumor-bearing rats resulted in efficient viral transduction of multifocal HCC lesions in their livers, tumor-selective viral replication, and extensive oncolysis. Importantly, no significant vector-associated toxicities were noted and, in particular, no damage to the hepatic parenchyma was seen. Finally, survival of vector-treated rats was substantially prolonged over that of animals in the control treatment group (p < 0.028). Thus, hepatic arterial administration of VSV is both effective and safe in an orthotopic animal model of multifocal HCC. The results suggest that oncolytic VSV can be developed into an effective and safe therapeutic modality for patients with multifocal HCC in the future.