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Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter

Gene Therapy volume 11, pages 645–648 (2004)Cite this article

A Corrigendum to this article was published on 07 February 2006

Abstract

Adenoviral vectors are considered to be good gene delivery vectors for cancer gene therapy due to their wide host tissue range and cell cycle-independent infectivity. However, the disadvantages include the lack of specificity for cancer cells and the high liver accumulation in vivo. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. We explored the CXCR4 promoter as a candidate to restrict adenoviral transgene expression to tumor cells with a low expression in host tissues. The luciferase activities in multiple cancer cell lines infected with recombinant adenovirus reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter exhibited relatively high transcriptional activity in a breast cancer cell line, MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65% (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both normal cell lines HFBC and HMEC. In addition, CXCR4 had a low expression of luciferase (0.32%) compared to that of the CMV promoter in mouse liver in vivo. The data also revealed that the CXCR4 promoter was a stronger tumor-specific promoter (TSP) than the Cox-2M promoter in primary melanomas obtained from two patients. The CXCR4 promoter is shown to have a ‘tumor-on’ and ‘liver-off’ status in vitro and in vivo, and CXCR4 may prove to be a good candidate TSP for cancer gene therapy approaches for melanoma and breast cancers.

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Acknowledgements

This study was supported by research grants from the National Institute of Health Grants: R01 CA83821, R01 HL67962, K12 HD01261-02 (WRHR) and 5P50 CA83591 (Ovarian SPORE Developmental Grant).

We thank Dr SL Michael for the kind gift of the construct pBSKCAT/CXCR4 1B/4-1, Dr S Boopana for the control cell line HFBC and Dr D Dieckmann for the two primary melanomas P-A and P-B.

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Authors and Affiliations

  1. Division of Human Gene Therapy, Departments of Medicine, Pathology, and The Gene Therapy Center, University of Alabama at Birmingham, AL, USA

    ZB Zhu, B Lu, L Kaliberova, B Liu, AA Rivera, DM Nettelbeck, PJ Mahasreshti, M Yamaoto & DT Curiel

  2. Department of Obstetrics and Gynecology, University of Alabama at Birmingham, AL, USA

    SK Makhija, CA Leath III & RD Alvarez

  3. Department of Pathology, University of Alabama at Birmingham, AL, USA

    M Wang

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  1. ZB Zhu
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  2. SK Makhija
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  3. B Lu
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Zhu, Z., Makhija, S., Lu, B. et al. Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter. Gene Ther 11, 645–648 (2004). https://doi.org/10.1038/sj.gt.3302089

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