An oncolytic adenovirus 11p vector expressing adenovirus death protein in the E1 region showed significant apoptosis and tumour-killing ability in metastatic prostate cells.

Haidong Wu,Ya-Fang Mei

doi:10.18632/oncotarget.26754

Abstract

The usefulness for cancer therapy of replication-competent adenoviral vectors expressing therapeutic genes from the E3 region has been evaluated, but few reports have described replication-competent adenoviruses with insertions at the E1 region in the full viral genome. We investigated in different prostate cancer cells the oncolytic efficacy of the replication-competent adenovirus 11p vectors expressing adenovirus death (RCAd11pADP) and red fluorescence (RCAd11pRFP) proteins from the upstream E1 region. ADP/RFP gene expression was 2-3 logs higher in PC3 and DU145 cells than in LNCaP and RWPE-1 cells. E1A protein expression in PC3 and DU145 cells was notably increased after infection with the RCAd11pADP or RCAd11pRFP vector compared with the Ad11pwt virus. Toxicity assays revealed 2-5-fold greater oncolytic effects of RCAd11pADP compared to Ad11pwt. Although all three viruses suppressed subcutaneous PC3 tumour growth in nude mice, RCAd11pRFP had greater oncolytic effects than did the Ad11pwt virus, and RCAd11pADP exhibited significant anti-tumour effects via apoptosis in a xenograft model. Interestingly, the apoptosis triggered by RCAd11pADP was markedly enhanced in comparison to that by the vector expressing ADP from E3 region. Taken together, our findings suggest that RCAd11pADP can potentially be used for the treatment of prostate metastases in clinical settings.

Highlights

Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in many western countries [1]
We investigated in different prostate cancer cells the oncolytic efficacy of the replication-competent adenovirus 11p vectors expressing adenovirus death (RCAd11pADP) and red fluorescence (RCAd11pRFP) proteins from the upstream E1 region
The genome sizes of the adenoviruses were as follows: RCAd11pADP, 36,105 bp, corresponding to an increase of 3.77% compared with the unmodified adenovirus 11 prototype (Ad11pwt) genome (34,794 bp); RCAd11pRFP, 36,504 bp, corresponding to an increase of 4.91% compared with the Ad11p genome

Summary

Introduction

Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in many western countries [1]. Prostate cancer occurs at a very high frequency in older men over 75 years of age. Radiotherapy and chemotherapy might improve the patient’s status, but most become tolerant to hormone therapy after a few years, resulting in the development of metastases. As the survival of patients with metastatic prostate disease remains very low, new alternative therapeutic methods are needed. Gene therapy has great promise for treating cancer, and the most commonly used vector is based on human adenovirus serotype 5 (Ad5), a virus that causes mild respiratory illness in infants but no disease in immunocompetent adults. Ad5 is one of the best-studied viruses, is genetically stable, does not integrate into the host genome and propagates in cell culture in large amounts [2]

Methods

Results

Conclusion