Pilot--Photon Microscopy Visualization of Adenoviral Infection/ Prostatic Tumor

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

The goal of this proposal is to develop a novel intravital imaging modality for androgen-independent prostate cancer. It is estimated that over 198,100 American men will be diagnosed with prostate cancer in year 2001 and 34,000 of them will die from this disease. For advanced prostate cancers, hormonal ablation is the only effective therapy available; however, the majority of patents will experience cancer recurrence and develop androgen-independent tumors. The mean survival of patients with androgen independent prostate cancer is about 18 months and is incurable at present. Therefore, there is an urgent need to develop novel treatment strategies to control androgen independent prostate cancer. Gene therapy is an attractive alternative therapy for androgen independent prostate cancer. Several clinical trials have been launched to evaluate the safety and efficacy of adenoviral-based gene therapy on prate cancer. The most exciting results come from the study of tumor/tissue restricted replication competent adenovirus. This strategy allows virus to propagate from limited infected cells to the whole tumor mass and overcomes the main problem of inadequate in vivo infectivity and biodistribution of adenovirus. However, how the viruses distribute and propagate in the tumor is not well studied. The objective of this pilot study is to visualize the virus infection and propagation inside the tumor using Intravital Dual Photon Confocal Fluorescence Optical Imaging Technology. This pilot study will develop a model system for the investigation of a better strategy to improve adenovirus-based gene delivery to the tumor and, thus, help to improve adenovirus-based gene therapy. Specific Aims: Specific Aim I will test whether we can visualize adenovirus infection in subcutaneous tumors using adenovirus expressing red fluorescence protein. Subcutaneous green fluorescent protein expressing prostate cancers will be established in nude mice and infected with adenovirus through intra tumoral injection or systemic delivery. Red fluorescence protein expressed in infected cells will be visualized with Dual Photon Confocal Fluorescence Optical Imaging. Specific Aim II will test whether the expression of adenovirus E1A proteins will alter tumor vasculature. Adenovirus E1A protein has been demonstrated to inhibit tumor angiogenesis and induce apoptosis. This aim intends to further investigate and enhance the effect of E1A protein on tumor vasculature. Specific Aim III will visualize adenovirus replication in the tumors and analyze how virus replication affects tumor vasculature. Replication competent adenovirus expressing red fluorescence protein will be constructed and used in this aim.