Study On Double-regulated Oncolytic Adenovirus Armed With Apoptin For Hepatocellular Carcinoma

Currently malignant tumors have become the first-leading lethiferous disease. Although the morbidity and mortality of tumor patients have increased dramatically each year, the survival rates of the majority of cancer patients have not been improved. Traditional therapies such as surgery, radiotherapy and chemotherapy were found very limited antitumor effect and tumor recurrent rates and mortality rates remain very high, which indicate that the development of traditional therapies have been trapped. Therefore, it is urgent to develop more effective and secure therapeutic programs to break the awkward situation that cancer can not be cured.As gene therapy and virotherapy for cancer treatment have well developed in these days, the biological therapy such as the conditionally replicating adenoviruses (oncolytic adenoviruses) has become a hot research. Prof. Liu then combines the advantages of gene therapy and virotherapy and proposes a novel strategy for cancer treatment named"Targeting Gene-Virotherapy of Cancer". The strategy is to incorporate one or more therapeutic genes into oncolytic viral vector, which has brought new light and hope for cancer treatment.Since the E1A and E1B play critical roles in regulating adenoviral replication, modifications were usually located in E1 region of adenoviral DNA. We can target diverse signal pathways by deleting E1B-55kDa or E1A-24bp, thus adenovirus can replicate only in tumor cells. We can also use the cancer or tissue specific promoters to replace the E1A or E1B wild-type promoters. Apoptin, a protein separated from avian viruses, is unable to induce apoptosis in non-transformed normal human cells.We introduced apoptin gene into a double-regulated oncolytic adenovirus Ad·eAFP-E1A-E1B(△55) and constructed Ad·eAFP-E1A-E1B(△55)-Apoptin. Our results showed that Ad·eAFP-E1A-E1B(△55)-Apoptin had excellent antitumor effects in vitro for human hepatocarcinoma cell lines. Furthermore, Ad·eAFP-E1A-E1B(△55)-Apoptin could also effectively inhibit the progression of the xenograft Huh-7 carcinoma in nude mice even the volume of tumors had already reached 450-500 mm~3. The IHC of hexon and TUNEL proved the adenovirus can specifically induce apoptosis and multiply in hepatocarcinoma cells. This study firstly used the double-regulated oncolytic adenovirus vector carrying apoptin to treat tumors and attained efficient anti-tumor effect, which provides treatment paradigm for cancer therapy.