Development and Pre-Clinical Evaluation of a Novel Prostate-Restricted Replication Competent Adenovirus-AD-IU-1
Final rept. 1 May 2003-30 Apr 2006
INDIANA UNIV AT INDIANAPOLIS SCHOOL OF MEDICINE
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Recently we generated a prostate specific chimeric promoter, called PSES, by combining the active prostate specific enhancers from PSA and PSMA genes which are prominently expressed in androgen independent prostate cancers. The goal of this research is to develop a novel therapeutic agent, Ad-IU-1, using PSES to control the replication of adenovirus and the expression of a therapeutic gene, herpes simplex thymidine kinase TK. AD-IU-1 replicate as efficient as a wild type adenovirus in PSAPSMA positive cells, but not in PSAPSMA negative cells. Prodrug GCV augmented Ad-IU-1s killing activity against PSAPSMA positive cells, but not PSAPSMA negative cells in vitro. Ad-IU-1 was more effective in inhibit the growth of androgen-independent CWR22rv tumors. Due to recent improvement in our adenoviral vector construction which allows us to insert a bigger transgene into the viral genome, we further investigated a fusing suicide gene, FCYttk, by combining two suicide genes, a yeast cytosine deaminase, FCY, and improved TK, ttk. FCYttk had a better killing activity than TK against prostate cancer cells. We are on the process of constructing FCYttk-armed prostate restricted replicative adenovirus for future clinical investigation.
- Anatomy and Physiology
- Medicine and Medical Research