This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Logg, C. R.
Right arrow Articles by Kasahara, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Logg, C. R.
Right arrow Articles by Kasahara, N.

 Previous Article  |  Next Article 

Journal of Virology, December 2002, p. 12783-12791, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12783-12791.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tissue-Specific Transcriptional Targeting of a Replication-Competent Retroviral Vector

Christopher R. Logg,1,2 Aki Logg,1 Robert J. Matusik,3 Bernard H. Bochner,4 and Noriyuki Kasahara1,2,5*

Institute for Genetic Medicine,1 Departments of Pathology,2 Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,5 Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,3 Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 100214

Received 12 April 2002/ Accepted 13 September 2002

The inability of replication-defective viral vectors to efficiently transduce tumor cells in vivo has prevented the successful application of such vectors in gene therapy of cancer. To address the need for more efficient gene delivery systems, we have developed replication-competent retroviral (RCR) vectors based on murine leukemia virus (MLV). We have previously shown that such vectors are capable of transducing solid tumors in vivo with very high efficiency. While the natural requirement of MLV infection for cell division imparts a certain degree of specificity for tumor cells, additional means for confining RCR vector replication to tumor cells are desirable. Here, we investigated the parameters critical for successful tissue-specific transcriptional control of RCR vector replication by replacing various lengths of the MLV enhancer/promoter with sequences derived either from the highly prostate-specific probasin (PB) promoter or from a more potent synthetic variant of the PB promoter. We assessed the transcriptional specificity of the resulting hybrid long terminal repeats (LTRs) and the cell type specificity and efficiency of replication of vectors containing these LTRs. Incorporation of PB promoter sequences effectively restricted transcription from the LTR to prostate-derived cells and imparted prostate-specific RCR vector replication but required the stronger synthetic promoter and retention of native MLV sequences in the vicinity of the TATA box for optimal replicative efficiency and specificity. Our results have thus identified promoter strength and positioning within the LTR as important determinants for achieving both high transduction efficiency and strict cell type specificity in transcriptionally targeted RCR vectors.

* Corresponding author. Mailing address: Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar St., CSC 240, Los Angeles, CA 90033. Phone: (323) 442-2099. Fax: (323) 442-2764. E-mail: kasahara{at}usc.edu.

Journal of Virology, December 2002, p. 12783-12791, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12783-12791.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Baranick, B. T., Lemp, N. A., Nagashima, J., Hiraoka, K., Kasahara, N., Logg, C. R. (2008). Splicing mediates the activity of four putative cellular internal ribosome entry sites. Proc. Natl. Acad. Sci. USA 105: 4733-4738 [Abstract] [Full Text]  
  • Paar, M., Schwab, S., Rosenfellner, D., Salmons, B., Gunzburg, W. H., Renner, M., Portsmouth, D. (2007). Effects of Viral Strain, Transgene Position, and Target Cell Type on Replication Kinetics, Genomic Stability, and Transgene Expression of Replication-Competent Murine Leukemia Virus-Based Vectors. J. Virol. 81: 6973-6983 [Abstract] [Full Text]  
  • Hiraoka, K., Kimura, T., Logg, C. R., Tai, C.-K., Haga, K., Lawson, G. W., Kasahara, N. (2007). Therapeutic Efficacy of Replication-Competent Retrovirus Vector-Mediated Suicide Gene Therapy in a Multifocal Colorectal Cancer Metastasis Model. Cancer Res. 67: 5345-5353 [Abstract] [Full Text]  
  • Hiraoka, K., Kimura, T., Logg, C. R., Kasahara, N. (2006). Tumor-Selective Gene Expression in a Hepatic Metastasis Model after Locoregional Delivery of a Replication-Competent Retrovirus Vector. Clin. Cancer Res. 12: 7108-7116 [Abstract] [Full Text]  
  • Metzl, C., Mischek, D., Salmons, B., Gunzburg, W. H., Renner, M., Portsmouth, D. (2006). Tissue- and Tumor-Specific Targeting of Murine Leukemia Virus-Based Replication-Competent Retroviral Vectors. J. Virol. 80: 7070-7078 [Abstract] [Full Text]  
  • Kubo, S., Seleme, M. d. C., Soifer, H. S., Perez, J. L. G., Moran, J. V., Kazazian, H. H. Jr., Kasahara, N. (2006). L1 retrotransposition in nondividing and primary human somatic cells. Proc. Natl. Acad. Sci. USA 103: 8036-8041 [Abstract] [Full Text]  
  • Hlavaty, J., Stracke, A., Klein, D., Salmons, B., Gunzburg, W. H., Renner, M. (2004). Multiple Modifications Allow High-Titer Production of Retroviral Vectors Carrying Heterologous Regulatory Elements. J. Virol. 78: 1384-1392 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»