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Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

Cancer Gene Therapy volume 17, pages 447–456 (2010)Cite this article

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Abstract

Gene therapy is being examined as a potential strategy for treating prostate cancer. Serotype 5 adenovirus (Ad.5) is routinely used as a vector for transgene delivery. However, the infectivity of Ad.5 is dependent on Coxsackie-adenovirus receptors (CARs); many tumor types show a reduction in this receptor in vivo, thereby limiting therapeutic gene transduction. Serotype chimerism is one approach to circumvent CAR deficiency; this strategy is used to generate an Ad.5/3-recombinant Ad that infects cancer cells through Ad.3 receptors in a CAR-independent manner. In this report, the enhanced transgene delivery and efficacy of Ad.5/3-recombinant virus was evaluated using an effective wide-spectrum anticancer therapeutic melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24). Our data show that in low CAR human prostate cancer cells (PC-3), a recombinant Ad.5/3 virus delivering mda-7/IL-24 (Ad.5/3-mda-7) is more efficacious than an Ad.5 virus encoding mda-7/IL-24 (Ad.5-mda-7) in infecting tumor cells, expressing MDA-7/IL-24 protein, inducing cancer-specific apoptosis, inhibiting in vivo tumor growth and exerting an antitumor ‘bystander’ effect in a nude mouse xenograft model. Considering the fact that Ad.5-mda-7 has shown significant objective responses in a phase I clinical trial for solid tumors, Ad.5/3-mda-7 is predicted to exert enhanced therapeutic benefit in patients with prostate cancer.

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Acknowledgements

This study was supported in part by NIH Grants P01 CA104177 and CA097318, the National Foundation for Cancer Research (NFCR), the Samuel Waxman Cancer Research Foundation, the Goldhirsh Foundation and the Dana Foundation. DS is the Harrison Endowed Scholar in the VCU Massey Cancer Center. PBF holds the Thelma Newmeyer Corman Chair in Cancer Research at the VCU Massey Cancer Center and is a SWCRF Investigator.

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Authors and Affiliations

  1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA

    R Dash, Z-z Su, S K Bhutia, B Azab, N Vozhilla, D Sarkar & P B Fisher

  2. Gene Therapy Center, University of Alabama in Birmingham, Birmingham, AL, USA

    I Dmitriev & D T Curiel

  3. Department of Biochemistry and Molecular Biology, VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA

    A Yacoub & P Dent

  4. VCU Institute of Molecular Medicine and VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA

    D Sarkar & P B Fisher

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Correspondence to P B Fisher.

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Dash, R., Dmitriev, I., Su, Zz. et al. Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells. Cancer Gene Ther 17, 447–456 (2010). https://doi.org/10.1038/cgt.2009.91

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