The objective of this project is to develop a highly effective system for intravesicle adenoviral-mediated gene delivery that will be translated into a novel approach for the therapy of superficial. A novel reproducible intravesicle model for human superficial bladder cancer in arrhythmic mice developed in our laboratory will be used to optimize gene transfer. Tumor cells transduced with the green-fluorescent protein (GFP) will be implanted into the bladders of mice. This will allow subsequent tumors to be visualized while the mouse is still living. We will measure GFP based fluorescence to quantitate tumor burden. Using this model, we will optimize the conditions and schedule of p53 gene therapy. These experiments will determine whether the simultaneous instillation of the detergent, Syn3, will enhance p53 gene transfer into tumor and normal urothelial cells. Furthermore, we will test our hypothesis that pretreatment with cisplatin will enhance the efficacy of p53 gene therapy. We will characterize the antitumor effect of a modified p53 construct with enhanced transcriptional activity that we hypothesize will have increased anti-tumor activity compared to wild type p53. In these experiments, we will evaluate p53 gene transfer by immunohistochemical analysis and will use immunohistochemistry and in situ to characterize the antitumor and bystander effects (angiogenesis and apoptosis) mediated by p53 gene therapy. We evaluate the mechanisms of the direct tumor cell and indirect bystander effects mediated by p53 gene therapy. The results of these preclinical studiers will be used to design a phase I trial of phase I trial of p53 gene therapy with Syn3.
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