Adenovirus-Mediated Expression of Truncated E2F-1 Suppresses Tumor Growth In Vitro and In Vivo

BACKGROUND: Adenovirus (Ad)-mediated E2F-1 gene transfer induces apoptosis in cancer cells in vitro and in vivo, but clinical application of E2F-1 in cancer gene therapy remains controversial because of the oncogenic potential of E2F-1. This barrier can be circumvented by using the truncated form of the E2F-1 gene (E2Ftr) (amino acids 1 through 375), which lacks the E2F-1 transactivation domain and cell cycle-promoting effects. METHODS: The authors constructed 3 adenoviral vectors that expressed E2Ftr under regulation of the tetracycline (Tet)-off system (AdTet-E2Ftr1, AdTet-E2Ftr2, and AdTet-E2Ftr3). These vectors were compared for E2Ftr expression and apoptosis induction in cancer cells and normal cells. E2Ftr antitumor activity in vivo also was assessed in a melanoma xenograft model. RESULTS: One of the 3 vectors, AdTet-E2Ftr3, had the highest E2Ftr protein expression levels, which were correlated with the greatest induction of apoptosis and inhibition of cancer cell growth. E2Ftr induced apoptosis in a variety of cancer cell lines independent of p53 status with little cytotoxicity in normal cell lines. In a mouse melanoma xenograft model, AdTet-E2Ftr3 exhibited an approximately 80% decrease in tumor size compared with controls in vivo. CONCLUSIONS: The current results indicated that AdTet-E2Ftr3 is a novel anticancer agent that has significant therapeutic activity in vitro and in vivo. Cancer 2010;116:4420-32. (C) 2010 American Cancer Society.