731. Completely Elimination of Xenograft SW620 Cancer by Combined Tumor Targeting MnSOD and Trail Genes

Abstract

MnSOD is a latent tumor suppressor gene. In order to studies the therapeutic effect and mechanisms of MnSOD action, the tumor-specific replication-competent adenovirus pZD55 (E1B55 KD deleted adenovirus) was constructed and two human genes were inserted into it to form ZD55-MnSOD and ZD55-Trail. After studying, it was found the first time that the antitumor effect of ZD55-MnSOD is about 1000 fold than that of Ad-MnSOD. Further more by the combination of ZD55-MnSOD and ZD55-Trail, which was called before as Targeting Dual Gene-ViroTherapy strategy, then all the established xenograft SW620 solid tumor could be completely eliminated. This is an excellently date for the tumor killing effect of combined ZD55-MnSOD and ZD55-Trail, which was due to the compensative and synergic effect between ZD55-MnSOD and ZD55-Trail and also due to their apoptosis when assayed by apoptotic method, such as DNA fragmentation, FACS or TUNEL. The overexpression of MnSOD accumulated the generation of H2O2, which could arrest cell cycle and induce apoptosis. The overexpressed Bax could result from the overexpression of MnSOD and Trail. The MnSOD could induced the releasing of AIF and cyto C, and then caspase-9 and caspase-3 were cleaved separately, while Trail could induced the cleavage of caspase-8. These results suggest that the antitumor efficiency of ZD55-MnSOD and the combination of ZD55-MnSOD with ZD55-Trail were all mediated by apoptosis.