Comparison of Prostate-Specific Promoters and the Use of PSP-Driven Virotherapy for Prostate Cancer

Yi Lu,Guimin Chang,Jun Zhang,Yu Zhang

doi:10.1155/2013/624632

Yi Lu, Guimin Chang + Show 2 more

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https://doi.org/10.1155/2013/624632

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Abstract

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men today. Although virus-based gene therapy is a promising strategy to combat advanced prostate cancer, its current effectiveness is limited partially due to inefficient cellular transduction in vivo. To overcome this obstacle, conditional oncolytic viruses (such as conditional replication adenovirus (CRAD)) are developed to specifically target prostate without (or with minimal) systemic toxicity due to viral self-replication. In this study, we have analyzed and compared three prostate-specific promoters (PSA, probasin, and MMTV LTR) for their specificity and activity both in vitro and in vivo. Both mice model with xenograft prostate tumor model and canine model were used. The best PSP was selected to construct a prostate-specific oncolytic adenovirus (CRAD) by controlling the adenoviral E1 region. The efficacy and specificity of CRAD on prostate cancer cells were examined in cell culture and animal models.

Highlights

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths in American men today with an estimated 241,740 new cases of prostate cancer and 28,170 deaths estimated in year 2012 [1]
We found that all adenoviral vector-injected prostates had an intense 860 bp signal band on agarose gel, con rming that the majority of adenoviral transduction occurred in the prostate
Adenovirus may disseminate to other organs and tissues, primarily bladder and vas deferens. e presence of adenoviral DNA in heart, blood vessels, and liver tissues may be explained by the fact that these organs overall receive a higher percentage of cardiac output than other organs

Summary

Introduction

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths in American men today with an estimated 241,740 new cases of prostate cancer and 28,170 deaths estimated in year 2012 [1]. Virus-based gene therapy is a promising strategy to combat advanced prostate cancer, its current effectiveness is limited partially due to inefficient cellular transduction by therapeutic viral vectors in vivo. To overcome this obstacle, conditional oncolytic viruses (such as conditional replication adenovirus (CRAD)) are developed to speci cally target prostate without (or with minimal) systemic toxicity due to viral “oncolytic” self-replication. Erefore, strategies to use conditional oncolytic virus, or the so-called attenuated replication-competent viruses, to speci cally target prostate tissue have been developed [2,3,4]. Released virus is able to infect neighboring cells until all susceptible cells are eliminated. eoretically, a large tumor burden could be effectively eradicated using a small dose of an oncolytic virus. erefore, strategies to use conditional oncolytic virus, or the so-called attenuated replication-competent viruses, to speci cally target prostate tissue have been developed [2,3,4]. e idea behind this study is to place the Ad5 E1 region in cis complementation (i.e., use E1 as a transgene) back into an E1-deleted, replication-defective adenovirus under the control of a prostate-speci c promoter (PSP). us, E1 protein expression will be con ned strictly to the prostate tissues and render this a conditional oncolytic virus (CRAD) within the prostate

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