The adenovirus type-5 E1A was reported originally as an oncogene, which could cooperate with other viral and cellular oncogenes to transform primary culture cells, however, E1A has not been associated with human malignancies despite extensive studies trying to identify such a link. Instead, the type-5 E1A was shown to suppress tumorigenicity and experimental metastasis of rodent cells transformed by the ras oncogene and by the neu oncogene and metastasis of certain human cancer cell lines. In addition to the tumor suppressor activities, expression of the E1A gene has also been shown to increase sensitivity to a variety of apoptotic stimuli-induced apoptosis. Currently, a phase I E1A gene therapy protocol for human breast and ovarian cancers was completed and a phase II clinical trial is undergoing, therefore, we plan to develop an alternative E1A mutant construct to maximize E1A therapeutic effects while minimizing its potential side-effects for cancer gene therapy. To this end, we established a serials deletion mutation of E1A and evaluated their anti-tumor activities in vitro and in vivo. We identified that a mutant construct of E1A worked as good as that of the wild-type E1A in terms of repressing tumor growth and sensitization to chemotherapy in cell culture in vitro and in an orthotopic breast cancer xenograft model in vivo in the setting of a systemic gene therapy. Our results provided the feasibility for further evaluation of this mutant construct for the treatment of human cancer in the future.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]