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

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.

• Authors: R Dash, I Dmitriev, Z-z Su, S K Bhutia, B Azab, N Vozhilla, A Yacoub, P Dent, D T Curiel, D Sarkar, P B Fisher
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 17 Issue 7 Pg. 447-56 (Jul 2010) ISSN: 1476-5500 [Electronic] England
• PMID: 20150932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CLMP protein, human
• CLMP protein, mouse
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Interleukins
• Receptors, Virus
• interleukin-24

Topics

• Adenoviridae (genetics)
• Animals
• Cell Line, Tumor
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Genetic Therapy (methods)
• Humans
• Immunohistochemistry
• Interleukins (biosynthesis, genetics)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (genetics, therapy)
• Receptors, Virus (metabolism)
• Transgenes
• Xenograft Model Antitumor Assays