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Engineering conditionally replication-competent adenoviral vectors carrying the cytosine deaminase gene increases the infectivity and therapeutic effect for breast cancer gene therapy

Cancer Gene Therapy volume 13, pages 346–356 (2006)Cite this article

Abstract

We constructed a conditionally replication-competent adenoviral vector Ad.Lp-CD-IRES-E1A(control) in which the expression of both the prodrug-activating cytosine deaminase gene and the viral replication E1A gene were driven by the L-plastin tumor-specific promoter. In order to overcome the low infectivity of the adenoviral vectors for breast cancer cells, and to increase the safety and efficacy for cancer gene therapy, this vector was further modified on a transductional level by simultaneously ablating the native tropism of the vector to the primary CAR receptor and inserting a RGD-4C peptide into the HI loop of the fiber, which allows the vector to use the αvβ3 and αvβ5 receptors as alternative receptors. The resulting vector was named Ad.Lp-CD-IRES-E1A(MRGD). The transduction efficiency of the vector for breast cancer cell lines which have low expression level of CAR was increased both in vitro and in vivo. The Ad.Lp-CD-IRES-E1A(MRGD) vector produces a higher vector particle yield and a greater cytotoxic effect in tumor cells which have a low expression level of CAR, than did the Ad.Lp-CD-IRES-E1A(control) vector. Intratumoral injection of the Ad.Lp-CD-IRES-E1A(MRGD) vector following the intraperitoneal injection of 5FC into xenotransplanted human breast cancer cell lines which have low expression level of CAR led to greater degree of tumor regression in vivo than did the intratumoral injection of control adenoviral vectors not so modified.

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Acknowledgements

This work was supported by a gift from the Sidney Kimmel Foundation, the Breast Cancer Research Foundation, the US Army Breast Cancer Research Program (DAMD 17-99-9477 and BC 022063), the Sidney Kimmel Cancer Center Vaccine Fund, the Anthony Dewitt Frost Melanoma Research Fund, the Audrey Demas Melanoma Research Fund, the Brian Schultz Cancer Research Fund, and the George and Barbara Bush Leukemia Research Foundation.

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  1. Sidney Kimmel Cancer Center, San Diego, CA, USA

    Y Liu, T Ye, J Maynard, H Akbulut & A Deisseroth

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Correspondence to A Deisseroth.

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Liu, Y., Ye, T., Maynard, J. et al. Engineering conditionally replication-competent adenoviral vectors carrying the cytosine deaminase gene increases the infectivity and therapeutic effect for breast cancer gene therapy. Cancer Gene Ther 13, 346–356 (2006). https://doi.org/10.1038/sj.cgt.7700906

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