Study On E1a, E1b Double-restricted Oncolytic Adenovirus Armed With Il-24 For Cancer Therapy

Currently malignant tumors have taken over the cardiovascular and cerebrovascular diseases and become the first-leading lethiferous disease. In the worldwide, the morbidity and mortality of tumor patients have increased dramatically each year, and the 5-year survival rates of the majority of cancer patients have not been improved. Traditional therapies such as surgery, radiotherapy and chemotherapy were found to no avail and tumor recurrent rates and mortality rates remain very high, which indicate that the development of traditional therapies has been trapped. Therefore, it is imperative to develop more effective and secure therapeutic programs to break the"curse"that cancer cannot be cured.As gene therapy and viroherapy 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 viroherapy and proposes a novel strategy for cancer treatment named"Cancer Targeting Gene-Virotherapy". 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 abnormal signal pathways in tumor cells by deleting E1B-55kD or E1A-24bp of adenoviral genome. Besides, we can use the cancer or tissue specific promoters to replace the E1A or E1B wild-type promoter. Mda-7/IL-24(melanoma differentiation associated gene-7/interleukin-24)is a new multifunctional cytokine with the ability of suppressing many tumor types. IL-24 can selectively induce apoptosis of tumor cells and leave normal cells unaffected, and it also can induce immune response and suppress tumor angiogenesis. Our lab has successfully constructed two E1 single-restricted oncolytic adenovirus, ZD55-IL-24(deletion of E1B 55kD)and Ad.sp- E1A(△24)-IL-24(deletion of E1A 24bp). Results showed that both could effectively suppress tumors in vitro and in vivo experiments.We introduced IL-24 into the E1A, E1B double-restricted oncolytic adenovirus and constructed the Ad·sp·E1A_(△24)·E1B_(△55)·IL-24. Data showed that Ad·sp·E1A_(△24)·E1B_(△55)·IL-24 had excellent antitumor effect in vitro for human lung, nasopharyngeal, liver, colorectal, cervical carcinoma cell lines. Furthermore, Ad·sp·E1A_(△24)·E1B_(△55)·IL-24 could also effectively inhibit the progression of the xenograft NCI-H460 carcinoma in nude mice. This study firstly used the E1A and E1B double-restricted oncolytic adenovirus vector carrying IL-24 to treat tumors and attained efficient anti-tumor effect, which provides an experimental foundation for cancer therapy.