Replication efficiency of oncolytic vaccinia virus in cell cultures prognosticates the virulence and antitumor efficacy in mice

Journal of Translational Medicine

Research

Nanhai G Chen¹  Qian Zhang¹  Yong A Yu¹  Aladar A Szalay² 

[1] Genelux Corporation, San Diego Science Center, 92109, San Diego, CA, USA;Department of Radiation Oncology, Rebecca and John Moores Comprehensive Cancer Center, University of California, 92093, San Diego, CA, USA;Genelux Corporation, San Diego Science Center, 92109, San Diego, CA, USA;Department of Radiation Oncology, Rebecca and John Moores Comprehensive Cancer Center, University of California, 92093, San Diego, CA, USA;Rudolph Virchow Center for Experimental Biomedicine, Department of Biochemistry and Institute for Molecular Infection Biology, University of Würzburg, D-97074, Würzburg, Germany;

关键词: GLV-1h68;    modulation of virus replication;    GI-101A tumor xenografts;    oncolytic virotherapy;   

DOI  :  10.1186/1479-5876-9-164

 received in 2011-09-12, accepted in 2011-09-27,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundWe have shown that insertion of the three vaccinia virus (VACV) promoter-driven foreign gene expression cassettes encoding Renilla luciferase-Aequorea GFP fusion protein, β-galactosidase, and β-glucuronidase into the F14.5L, J2R, and A56R loci of the VACV LIVP genome, respectively, results in a highly attenuated mutant strain GLV-1h68. This strain shows tumor-specific replication and is capable of eradicating tumors with little or no virulence in mice. This study aimed to distinguish the contribution of added VACV promoter-driven transcriptional units as inserts from the effects of insertional inactivation of three viral genes, and to determine the correlation between replication efficiency of oncolytic vaccinia virus in cell cultures and the virulence and antitumor efficacy in miceMethodsA series of recombinant VACV strains was generated by replacing one, two, or all three of the expression cassettes in GLV-1h68 with short non-coding DNA sequences. The replication efficiency and tumor cell killing capacity of these newly generated VACV strains were compared with those of the parent virus GLV-1h68 in cell cultures. The virus replication efficiency in tumors and antitumor efficacy as well as the virulence were evaluated in nu/nu (nude) mice bearing human breast tumor xenografts.Resultswe found that virus replication efficiency increased with removal of each of the expression cassettes. The increase in virus replication efficiency was proportionate to the strength of removed VACV promoters linked to foreign genes. The replication efficiency of the new VACV strains paralleled their cytotoxicity in cell cultures. The increased replication efficiency in tumor xenografts resulted in enhanced antitumor efficacy in nude mice. Similarly, the enhanced virus replication efficiency was indicative of increased virulence in nude mice.ConclusionsThese data demonstrated that insertion of VACV promoter-driven transcriptional units into the viral genome for the purpose of insertional mutagenesis did modulate the efficiency of virus replication together with antitumor efficacy as well as virulence. Replication efficiency of oncolytic VACV in cell cultures can predict the virulence and therapeutic efficacy in nude mice. These findings may be essential for rational design of safe and potent VACV strains for vaccination and virotherapy of cancer in humans and animals.

【 授权许可】

Unknown   
© Chen et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.