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

被引:22
作者
Chen, Nanhai G. [1 ,2 ]
Yu, Yong A. [1 ,2 ]
Zhang, Qian [1 ,2 ]
Szalay, Aladar A. [1 ,2 ,3 ,4 ]
机构
[1] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA
[2] Univ Calif San Diego, Rebecca & John Moores Comprehens Canc Ctr, Dept Radiat Oncol, San Diego, CA 92093 USA
[3] Univ Wurzburg, Dept Biochem, Rudolph Virchow Ctr Expt Biomed, D-97074 Wurzburg, Germany
[4] Univ Wurzburg, Inst Mol Infect Biol, D-97074 Wurzburg, Germany
关键词
GLV-1h68; modulation of virus replication; GI-101A tumor xenografts; oncolytic virotherapy; RECOMBINANT VACCINIA; NUDE-MICE; THERAPY; REGRESSION; GLV-1H68; DELETION; PROTEIN; CANCER; AGENT;
D O I
10.1186/1479-5876-9-164
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
100103 [病原生物学]; 100218 [急诊医学];
摘要
Background: We have shown that insertion of the three vaccinia virus (VACV) promoter-driven foreign gene expression cassettes encoding Renilla luciferase-Aequorea GFP fusion protein, beta-galactosidase, and beta-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 mice Methods: A 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. Results: we 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. Conclusions: These 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.
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页数:11
相关论文
共 33 条
[1]
[Anonymous], 1988, Human Monkeypox
[2]
[Anonymous], CANC FACTS FIGURES 2
[3]
[Anonymous], CANC FACT SHEET
[4]
Targeting Tumor Vasculature With an Oncolytic Virus [J].
Breitbach, Caroline J. ;
De Silva, Naomi S. ;
Falls, Theresa J. ;
Aladl, Usaf ;
Evgin, Laura ;
Paterson, Jennifer ;
Sun, Yang Yang ;
Roy, Dominic G. ;
Rintoul, Julia L. ;
Daneshmand, Manijeh ;
Parato, Kelley ;
Stanford, Marianne M. ;
Lichty, Brian D. ;
Fenster, Aaron ;
Kirn, David ;
Atkins, Harold ;
Bell, John C. .
MOLECULAR THERAPY, 2011, 19 (05) :886-894
[5]
DELETION OF THE VACCINIA VIRUS GROWTH-FACTOR GENE REDUCES VIRUS VIRULENCE [J].
BULLER, RML ;
CHAKRABARTI, S ;
COOPER, JA ;
TWARDZIK, DR ;
MOSS, B .
JOURNAL OF VIROLOGY, 1988, 62 (03) :866-874
[6]
Compact, synthetic, vaccinia virus early/late promoter for protein expression [J].
Chakrabarti, S ;
Sisler, JR ;
Moss, B .
BIOTECHNIQUES, 1997, 23 (06) :1094-1097
[7]
A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging [J].
Chen, Nanhai ;
Zhang, Qian ;
Yu, Yong A. ;
Stritzker, Jochen ;
Brader, Peter ;
Schirbel, Andreas ;
Samnick, Samuel ;
Serganova, Inna ;
Blasberg, Ronald ;
Fong, Yuman ;
Szalay, Aladar A. .
MOLECULAR MEDICINE, 2009, 15 (5-6) :144-151
[8]
Chen NG, 2011, CANCER GROW PROG-DOR, V13, P295, DOI 10.1007/978-90-481-9704-0_16
[9]
Oncolytic vaccinia virus: a theranostic agent for cancer [J].
Chen, Nanhai G. ;
Szalay, Aladar A. .
FUTURE VIROLOGY, 2010, 5 (06) :763-784
[10]
Use of an oncolytic vaccinia virus for the treatment of canine breast cancer in nude mice: preclinical development of a therapeutic agent [J].
Gentschev, I. ;
Stritzker, J. ;
Hofmann, E. ;
Weibel, S. ;
Yu, Y. A. ;
Chen, N. ;
Zhang, Q. ;
Bullerdiek, J. ;
Nolte, I. ;
Szalay, A. A. .
CANCER GENE THERAPY, 2009, 16 (04) :320-328