Development and Pre-Clinical Evaluation of a Novel Prostate-Restricted Replication Competent Adenovirus-AD-IU-1

摘要

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 PSA/PSMA positive cells, but not in PSA/PSMA negative cells. Prodrug GCV augmented Ad-IU-1's killing activity against PSA/PSMA positive cells, but not PSA/PSMA 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.