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A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

Cancer Gene Therapy volume 12, pages 935–946 (2005)Cite this article

Abstract

Typically, gene transfer strategies utilize a promoter/transgene arrangement that treat these elements independently and do not offer any interplay between them. Our goal was to establish a promoter/transgene combination that would result in improvement in both expression and therapeutic effect by utilizing the transcriptional properties of p53 to drive its own expression as well as act as a tumor suppressor. The pCL retroviral system was modified in the U3 region of the 3′ LTR by the addition of a p53-responsive sequence (the PG element), creating the pCLPG system. Upon reverse transcription, the 5′ LTR is converted, as shown here, to a p53-dependent promoter. We also show, using a temperature-sensitive model, that the pCLPG system could be driven by p53 encoded within the virus construct and expression was modulated depending on the p53 phenotype, demonstrating a regulatory feedback loop. Moreover, the pCLPG system was shown to express the transgene at a higher level and to inhibit tumor cell proliferation more robustly than the original pCL system. This novel system employs the transgene to serve two purposes, drive viral expression and inhibit tumor cell proliferation. The pCLPG vectors represent a new gene transfer strategy of synergizing the promoter and transgene activities.

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Acknowledgements

We thank Moshe Oren and Bert Vogelstein for kindly providing plasmids. This work was supported by FAPESP (98/15120-0, ECS and 00/12156-5, BES).

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Authors and Affiliations

  1. Heart Institute, InCor, University of São Paulo School of Medicine, Brazil

    Bryan E Strauss & Marcio C Bajgelman

  2. Program in Biotechnology, Biomedical Sciences Institute, University of São Paulo, Brazil

    Bryan E Strauss, Marcio C Bajgelman & Eugenia Costanzi-Strauss

  3. Department of Cell Biology and Development, Biomedical Sciences Institute, University of São Paulo, Brazil

    Eugenia Costanzi-Strauss

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  1. Bryan E Strauss
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  3. Eugenia Costanzi-Strauss
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Correspondence to Bryan E Strauss.

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Strauss, B., Bajgelman, M. & Costanzi-Strauss, E. A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition. Cancer Gene Ther 12, 935–946 (2005). https://doi.org/10.1038/sj.cgt.7700846

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