Abstract
Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential.
Highlights
Prostate cancer is a major health problem for men in Western societies
In prostate cancer cell lines 22RV1 and DU145, the cytoxicity of Ad.DD3.D55 was comparable to the single-regulated adenovirus Ad.DD3 and Ad.D55
Different recombinant promoters have been generated based on the Prostate Cancer-specific activity of a promoter or enhancer to increase the Prostate Cancer-specific activity of the promoter controlling the replication of the oncolytic virus [26,27,28,29]
Summary
Prostate cancer is a major health problem for men in Western societies. Each year, approximately 230,000 American males are diagnosed with prostate cancer and nearly 30,000 die from this disease [1,2]. The best available treatment for patients with the advanced disease is androgen ablation therapy, based on the observations of Huggins and Hodges [3] that clinical prostate cancer is under the trophic influence of male hormones. The adenoviral vector has been used as a transfer vehicle to introduce genes into cancer cells because it is more efficient than non-viral gene transfer methods [4,5]. Cancer-specific replication of the oncolytic vector, is absolutely required to prevent these problems. Two major strategies have been used to construct a replicative and cancer-specific oncolytic adenovirus. The E1B-55K gene, which was deleted in the oncolytic viruses ONYX015 and ZD55 [8,9,10], is required for viral replication in normal cells but is dispensable in cancer cells due to compensatory mechanisms. The oncolytic virus is highly replicated when the promoter is activated
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