Anti-tumor Activity In HCC Of A Triplex-regulated Replicative Adenovirus Sg511-pHSP70-IL24 With Mda7/IL24

The tumor's gene-viral therapy has been the hot spot in the field of tumor's biological therapy, among which replicative adenovirus is the hottest. However, because of the shortcomings of the adenovirus such as the low ability to target to cancer cells, the application of adenoviruses is heavily limited. Therefore, the key problem of the research of replicative adenovirus is how to improve the ability of targeting to cancer cells. Nowadays, there are two main methods to reach the goal.The first strategy is to regulate the duplication of the adenovirus, which would make the adenovirus replicate only in tumor cells. The second strategy is to change the adenovis's fiber protein, and this would cause the adenovirus exclusively infecting the tumor cells. Among adenovirus, adenovirus type 5 is one adenovirus vector that has been researched best, and also the most widely used vector. In order to make Ad5 replicate only in tumors, the most common method is to use some specific promoters to regulate the replication of the adenovirus's genome.The hTERT promoter and the HRE promoter have stronger activity in most tumor cells and little activity in nomal cells. Because of this, our team constructed a new vector containing hTERTp and HREp to regulate E1a and E1b, so that the virus will only replicate in tumor cells. B-group adenovirus type11 (Ad11) binds to cells via the expressed complement regulatory protein CD46. Because of the advantages of Ad11, we exchange the Ad5's fiber's knob and shaft with Ad11's fiber's knob and shaft. Combining the first strategy, we constructed adenovirus SG511, in which the hTERT promotor and the HRE promotor respectively regulate the expression of E1a and E1b, and it also has the Ad11's fiber.Liver cancer has the feature of high invasion and low curing rate, which makes it one of the most severe cancers.However, there are no effective therapeutic methods. Therefore, it is very important to develop a new effective therapeutic method. IL-24 is a cytokine that can inhibit the growth of a variety of tumors.Heat shock proteins can be induced in cells and organisms by excitable stimulation, among which HSP70 is the most conservative and most important. It is indicated that when cells are infected by adenovirus, HSP70 promoter will be induced by E1a. As E1a of SG511 constructed by our team can be only packaged in tumor cells, we make use of HSP70 promoter to regulate the expression of IL-24.In order to cure live cancer, we further combined gene therapy with viral therapy and constructed a brand new gene-viral therapeautic system SG511-pHSP70-IL-24. The in vitro experiments manifested that SG500-pHSP70-IL-24 can induce apoptosis of hepatoma carcinoma cell,but does not damnify normal cells.Its ability of oncolysis is markedly higher than SG511 without therapeutic genes and non-replicative adenovirus Ad-IL-24, while it has no adverse effect on normal cells.In conclusion,SG511-hHSP70-IL-24 exerts the potent anti-tumor efficacy and low side toxicity.It may have great utility as a therapeutic agent for different types of cancers in clinical trials in future.