Combining high selectivity of replication via CXCR4 promoter with fiber chimerism for effective adenoviral oncolysis in breast cancer

Authors

  • Mariam A. Stoff-Khalili,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
    2. Department of Obstetrics and Gynecology, University of Duesseldorf Medical Center, 40225 Duesseldorf, Germany
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  • Angel A. Rivera,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Alexander Stoff,

    Corresponding author
    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
    2. Department of Plastic and Reconstructive Surgery, Dreifaltigkeits-Hospital, 50389 Wesseling, Germany
    • Division of Human Gene Therapy, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, BMR2 502, Birmingham, AL 35294, USA

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    • Fax: 205-975-7476.

  • J. Michael Mathis,

    1. Gene Therapy Program, Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA
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  • Rodney P. Rocconi,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Qiana L. Matthews,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Michael T. Numnum,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Isabell Herrmann,

    1. Department of Obstetrics and Gynecology, University of Duesseldorf Medical Center, 40225 Duesseldorf, Germany
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  • Peter Dall,

    1. Department of Obstetrics and Gynecology, University of Duesseldorf Medical Center, 40225 Duesseldorf, Germany
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  • Devin E. Eckhoff,

    1. Division of Transplantation, University of Alabama at Birmingham, Birmingham, AL
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  • Joanne T. Douglas,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Gene P. Siegal,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • Zeng B. Zhu,

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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  • David T. Curiel

    1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL
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Abstract

Conditionally replicative adenoviruses (CRAds) represent novel therapeutic agents that have been recently applied in the context of breast cancer therapy. However, deficiencies in the ability of the adenovirus to infect target tumor cells and to specifically replicate within the tumor target represent key deficiencies preventing the realization of the full potential of this therapeutic approach. Minimal expression of the adenovirus serotype 5 (Ad5) receptor CAR (coxsackie and adenovirus receptor) on breast cancer cells represents a major limitation for Ad5-based virotherapy. Genetic fiber chimerism is a method to alter the tropism of Ad5-based CRAds to achieve CAR-independent infectivity of tumor cells. Here, we describe the use of a CRAd with cancer specific transcriptional control of the essential Ad5 E1A gene using the human CXCR4 gene promoter. We further modified the fiber protein of this agent by switching the knob domain with that of the adenovirus serotype 3. The oncolytic activity of this 5/3 fiber-modified CRAd was studied in breast cancer cell lines, primary breast cancer and human liver tissue slices from patients, and in a xenograft breast cancer mouse model. This infectivity enhanced CRAd agent showed improved replication and killing in breast cancer cells in vitro and in vivo with a remarkable specificity profile that was strongly attenuated in nonbreast cancer cells, as well as in normal human breast and liver tissues. In conclusion, utilization of a CRAd that combined infectivity enhancement strategies and transcriptional targeting improved the CRAd-based antineoplastic effects for breast cancer therapy. © 2006 Wiley-Liss, Inc.

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