PSES-a Novel Prostate Specific Chimeric Enhancer for Prostate Cancer Gene Therapy

摘要

Recently we generated a chemic prostate specific promoter, called PSES, by combining the enhancer elements from the PSA and PSMA genes. Based on PSES, we developed a prostate-restricted replicative adenovirus (PRRA), called AdE4PSESE1a. AdE4PSESE1a only replicated in PSA/PSMA positive prostate cancer cells or cells expressing adenoviral E1 and E4 proteins. AdE4PSESE1a only partially inhibited tumor growth when tested in animals. Then we armed AdE4PSESE1a with TRAIL to make AD-IU-2. Ad-IU-2 retains the prostate specificity of AdE4PSESE1a and expresses TRAIL only in PSA/PSMA positive cells. Ad-IU-2 demonstrated better in vitro cell killing activity and tumor killing activity in vivo than AdE4PSESE1a against PSA/PSMA positive prostate cancers. We also tested whether antiangiogenic factor EndoAngio (an endostatin- angiostatin fusion protein) can slow down tumor growth to give AdE4PSESE1a enough time to eradicate a tumor. We found that coinjection of an EndoAngioexpressing replication defective adenovirus, AdEndoAngio, with AdE4PSESE1a would be able to eliminate 7 of 8 treated tumors. We incorporated EndoAngio expression cassette into AdE4PSESE1a to make an antiangiogenic PRRA.