Therapeutic efficacy of an hTERT promoter-driven oncolytic adenovirus that expresses apoptin in gastric carcinoma

Abstract

The efficacy and specificity of treatment are the major challenges for cancer gene therapy. Oncolytic virotherapy is an attractive drug delivery platform of cancer gene therapy. Previous studies have determined that apoptin is a p53-independent, Bcl-2-insensitive apoptotic protein that has the ability to induce apoptosis specifically in tumor cells. In this study, we show that the administration of a dual cancer-specific oncolytic adenovirus construct, Ad-hTERT-E1a-apoptin [in which the adenovirus early region 1a (E1a) gene is driven by the cancer-specific promoter of human telomerase reverse transcriptase (hTERT) and that expresses apoptin simultaneously], suppresses tumor growth in gastric carcinoma cells in vitro and reduces the tumor burden in vivo in xenografted nude mice. The observation that infection with the Ad-hTERT-E1a-apoptin construct significantly inhibited the growth of gastric cancer cells and protected normal human gastric epithelium from growth inhibition confirmed the induction of cancer cell-selective adenovirus replication, growth inhibition and apoptosis by this therapeutic approach. In vivo assays were performed using BALB/c nude mice that had established primary tumors. Subcutaneous primary tumor volume was reduced not only in the intratumoral injection group but also in the systemic delivery mice following treatment with Ad-hTERT-E1a-apoptin. Furthermore, treatment of primary models with Ad-hTERT-E1a-apoptin increased the mouse survival time. These data reinforce previous research and highlight the potential therapeutic application of Ad-hTERT-E1a-apoptin for the treatment of neoplastic diseases in clinical trials.

Viral genes as oncolytic agents for cancer therapy

“…The safety profiling of conditionally replicating adenovirus shows excellent results and seems to be completely safe [182]. Moreover, various other studies proved effectiveness of apoptin in human xenograft of gastric cancer [183], bladder cancer [184], hepatomas [185] and prostate cancer [186] in nude mice model and against oral cancer in a mouse model [187]. However, prior immunity to adenovirus may hamper the effectiveness of the adenoviral-mediated transgene transfer; hence, other viral vectors have also been tested [188].…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Zhu et al constructed a TRAIL-expressing OAd, which can efficiently kill triplenegative breast cancer cell lines in vitro without damaging normal cells and efficiently inhibit the growth of tumors in animal experiments [139]. Similarly, apoptin can induce the apoptosis of tumor cells but not that of normal cells, and apoptin-expressing OAd can effectively inhibit the growth of gastric carcinoma cells [143].…”

Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

“…For example, the E1A region was replaced with CAV apoptin gene and this method of delivery has been demonstrated to be very successful in a range of cancer cell lines and mouse models [100,[164][165][166][167] Conditionally replicative adenoviral vectors have also been utilised. CAV-Apoptin was delivered in this way to gastric and hepatocarcinoma cells [168][169][170].…”