Journal
CANCER GENE THERAPY
Volume 17, Issue 7, Pages 447-456Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cgt.2009.91
Keywords
Coxsackie-adenovirus receptors; mda-7/IL-24; tropism-modified adenoviruses; PC-3
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Funding
- NIH [P01 CA104177, CA097318]
- National Foundation for Cancer Research (NFCR)
- Samuel Waxman Cancer Research Foundation
- Goldhirsh Foundation
- Dana Foundation
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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. Cancer Gene Therapy (2010) 17, 447-456; doi:10.1038/cgt.2009.91; published online 12 February 2010
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