Study On CEA-driven Oncolytic Adenovirus Carrying ST13 Gene For Colorectal Cancer Therapy

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. With the improvement of people's living standards and the change of dietary structure with high in protein and fat and low in fiber in our country, the trend of colorectal cancer mortality rate is steadily rising. Due to various reasons, the curative effect of the traditional treatment methods is limited. So the novel biological therapy for colorectal cancer shows new prospect."Targeting Gene-Virotherapy of Cancer", which combines the advantages both gene therapy and viroherapy, was a novel strategy for cancer treatment raised by Prof. Liu initially. Enhancing the ability of virus tumor-specific proliferation and carrying standout therapeutic genes will be the key points to achieve the best therapeutic efficacy.Since the E1A is one of the key elements to control the adenoviral replication, the deletion of 24 bp(E1A_△24) could limit the adenovirus replicating only in tumor cells whose pRb pathway is abnormal. Many researches have confirmed that carcinoembryonic antigen is high expressed in colorectal cancer. Therefore, Replacing the E1A wild-type promoter with the tumor tissue specific CEA promoter, virus tumor-specific proliferation can be achieved for colorectal cancer.ST13 has been identified as a cofactor of heat shock protein Hsp70, which can exerts antitumor activity. The expression of ST13 is down-regulation in colorectal cancer. Many studies have confirmed that ST13 could promote the apoptosis of colorectal carcinoma cells.Based on the improve strategy above-mentioned, we inserted ST13 gene into the adenovirus vector, constructed the recombinant oncolytic adenovirus Ad·(ST13)CEA·E1A_△24. Data showed that the recombinant adenovirus had more excellent antitumor effect in vitro for colorectal carcinoma cell lines than human cervical carcinoma cell line Hela, which was CEA-negative. The result suggested that CEA promoter had higher initiating activity in CEA-positive cell lines. In the meantime, the recombinant adenovirus carrying ST13 played more excellent killing effect. In addition, the recombinant adenovirus was no or little damage on normal cell lines. All these results demonstrated the efficacy and the safety of the recombinant adenovirus. Furthermore, Ad·(ST13)CEA·E1A_△24could also effectively inhibit the progression of the xenograft SW620 colon carcinoma in nude mice and dramatically improved the survival time of nude mice bearing cancer. We further explored the way of cell death and the anti-tumor mechanism induced by Ad·(ST13)CEA·E1A_△24.In conclusion, the recombinant oncolytic adenovirus Ad·(ST13)CEA·E1A_△24 has excellent therapeutic effect on colorectal cancer, which provides us a new choose for colorectal cancer clinical treatment.