Chimeric adenovirus vector enhances HSV-tk gene therapy for bladder cancer.

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We investigated the new treatment modality for bladder cancer. We tested that the transduction efficacy of adenovirus (Ad)-mediated bladder cancer gene therapy would be enhanced with the use of a novel chimeric Ad vector that utilizes a CAR-independent entry mechanism. A chimeric Ad vector expressing herpes simplex virus I thymidine kinase (HSV-tk) was constructed by Ad35 fiber into an Ad5 backbone (Ad5/F35). In vitro experiment Ad5/F35 with HSV-tk was up to 30 times more effective than Ad5HSV-tk in terms of cell death in CAR-negative cells and equally efficient in CAR-positive cells. Experimental group in vivo was categorized as 11 groups consisted of control, GFP infection only, GCV administration only, Ad5HSV-tk (5×10^8PFU), Ad5F35HSV-tk (1×10^8, 5×10^8, 1×10^9 PFU), Ad5HSV-tk/GCV (5×10^8PFU), Ad5F35HSV-tk/GCV (1×10^8, 5×10^8, 1×10^9 PFU). We observed a 10-fold treatment effect with Ad5/F35HSV-tk over Ad5HSV-tk in growth suppression of CAR-negative bladder cancer animal models with comparable anti-tumor efficacy in CAR-positive cancer models. There were no side effect and toxicity in major organs. This finding demonstrates that the Ad5/F35 vector transduced bladder cancer cells independently of CAR status and augments HSV-tk suicide gene therapy in CAR-negative bladder cancer.In addition, we also investigated immunohistochemical staining using S100A2, S100A4 and p53 in bladder cancer specimens taken form radical cystectomy. These proteins were associated with bladder cancer stage, grade and prognosis. These findings suggested that S100A2, S100A4 and p53 would play a role as target protein for gene therapy. According to the results, we demonstrated potential alternative as target specific treatment for bladder cancer using chimeric adenovirus vector.