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Journal of Virology, November 2005, p. 13705-13713, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13705-13713.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Prophylactic Alpha Interferon Treatment Increases the Therapeutic Index of Oncolytic Vesicular Stomatitis Virus Virotherapy for Advanced Hepatocellular Carcinoma in Immune-Competent Rats

Katsunori Shinozaki,1,{ddagger} Oliver Ebert,1,{ddagger} Arief Suriawinata,2,{dagger} Swan N. Thung,2 and Savio L. C. Woo1*

Department of Gene and Cell Medicine,1 Department of Pathology, Mount Sinai School of Medicine, New York, New York2

Received 4 April 2005/ Accepted 22 July 2005

Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to substantially attenuated antiviral responses in many tumors. We have recently reported that recombinant VSV vector can be used as an effective oncolytic agent to safely treat multifocal hepatocellular carcinoma (HCC) in the livers of immune-competent rats via hepatic artery infusion. When administered at doses above the maximum tolerated dose (MTD), however, the animals suffered from neurotoxicity and/or acute lethal hepatotoxicity. Since VSV is extremely sensitive to the antiviral actions of alpha/beta interferon (IFN-{alpha}/ß) in normal cells, we tested if prophylactic treatment with rat IFN-{alpha} would enhance VSV safety without compromising treatment efficacy in tumor-bearing rats. We found that VSV retained its replication potential in human and rat HCC cells after preincubation with relatively high doses of rat and human IFN-{alpha} in vitro, and its MTD in tumor-bearing rats treated systemically with rat IFN-{alpha} at 66 IU/g body weight (BW), equivalent to a human IFN-{alpha} dose that is currently prescribed for patients with viral hepatitis, was elevated by more than 1/2 log unit. Furthermore, we demonstrate that intratumoral replication of VSV was not attenuated by administration of 66 IU/g BW rat IFN-{alpha}, as tumor response and survival advantage in VSV-treated rats in the presence or absence of rat IFN-{alpha} were equivalent. The results suggest that prophylactic rat IFN-{alpha} treatment elevates the therapeutic index of hepatic arterial VSV therapy for multifocal HCC in rats. Since human IFN-{alpha} is currently in clinical use, its prophylactic application should be considered in future clinical translational protocols for VSV-mediated oncolytic virotherapy as a novel therapeutic modality in patients with advanced HCC, as well as other types of cancer.

* Corresponding author. Mailing address: Department of Gene and Cell Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1496, New York, NY 10029-6574. Phone: (212) 824-7728. Fax: (212) 803-6740. E-mail: savio.woo{at}mssm.edu.

{ddagger} Both authors contributed equally.

{dagger} Present address: Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, N.H.

Journal of Virology, November 2005, p. 13705-13713, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13705-13713.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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