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Complete Elimination of Colorectal Tumor Xenograft by Combined Manganese Superoxide Dismutase with Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Gene Virotherapy

¹ Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; ² Xinyuan Institute of Medicine and Biotechnology, School of Life Science, Zhejiang Sci-Tech University, Hangzhou, China; ³ Department of Hematology, First Affiliated Hospital, Medical College, Zhejiang University; ⁴ Laboratory of Gene and Virus Therapy, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China; ⁵ Division of Hepatology and Gene Therapy, School of Medicine, Centro de Investigation Médica Aplicada, University of Navarra, Pamplona, Spain; and ⁶ Department of Internal Medicine, Transplant Research Program, University of California-Davis Medical Center, Sacramento, California

Requests for reprints: Xin Yuan Liu, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. Phone: 86-21-54921126; Fax: 86-21-54921126; E-mail: xyliu{at}sibs.ac.cn or Jian Wu, Department of Internal Medicine, Transplant Research Program, University of California, Davis Medical Center, Sacramento, CA 95817. Phone: 916-734-8071; Fax: 916-734-8097; E-mail: jdwu@ucdavis.edu.

Manganese superoxide dismutase (MnSOD) is a latent tumor suppressor gene. To investigate the therapeutic effect of MnSOD and its mechanisms, a replication-competent recombinant adenovirus with E1B 55-kDa gene deletion (ZD55) was constructed, and human MnSOD and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) genes were inserted to form ZD55-MnSOD and ZD55-TRAIL. ZD55-MnSOD exhibited an inhibition in tumor cell growth 1,000-fold greater than Ad-MnSOD. ZD55-TRAIL was shown to induce the MnSOD expression in SW620 cells. Accordingly, by the combined use of ZD55-MnSOD with ZD55-TRAIL (i.e., "dual gene virotherapy"), all established colorectal tumor xenografts were completely eliminated in nude mice. The evidence exists that the MnSOD overexpression led to a slower tumor cell growth both in vitro and in vivo as a result of apoptosis caused by MnSOD and TRAIL overexpression after adenoviral transduction. Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome c. Cytochrome c finally triggered apoptosis by activating caspase-9 and caspase-3 in apoptotic cascade. Bax-mediated apoptosis seems to be dependent on caspase-8 activation because the inhibition of caspase-8 prevented Bid processing and Bax translocation. In conclusion, our dual gene virotherapy completely eliminated colorectal tumor xenografts via enhanced apoptosis, and this novel strategy points toward a new direction of cancer treatment. (Cancer Res 2006; 66(8): 4291-8)