Cancer targeting gene-viro-therapy specific for liver cancer by α-fetoprotein-controlled oncolytic adenovirus expression of SOCS3 and IL-24.

The combination of gene therapy and virotherapy for cancer treatment has received close attention and has become a trend in the field of cancer biotherapy. A strategy called 'Cancer Targeting Gene-Viro-Therapy' (CTGVT) or 'Gene Armed Oncolytic Viral Therapy' (GAOVT) has been proposed, in which an antitumor gene is inserted into an oncolytic viral vector. In our previous study, a dual-regulated oncolytic adenovirus with enhanced safety for normal cells and strict liver cancer-targeting ability, designated Ad•enAFP•E1A•E1B (Δ55) (briefly Ad•enAFP•D55), was successfully constructed. In the current work, interleukin-24 (IL-24) and suppressor of cytokine signaling 3 (SOCS3) genes were packaged into Ad•enAFP•D55. The new constructs, Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3), showed improved tumoricidal activity in hepatoma cell lines compared with the oncolytic viral vector Ad•enAFP•D55. The co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) showed much better antitumor effect than Ad•enAFP•D55-(IL-24) or Ad•enAFP•D55-(SOCS3) alone both in vitro and in a nude mouse xenograft model. Moreover, our results also showed that blockade of the Jak/Stat3 pathway by Ad•enAFP•D55-(SOCS3) infection in HuH-7 cells could down-regulate some anti-apoptosis proteins, such as XIAP, Bcl-xL, and survivin, which might sensitize the cells to Ad•enAFP•D55-(IL-24)-induced apoptosis. These results indicate that co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) may serve as a candidate therapeutic approach for the treatment of liver cancer.