A novel, conditionally replicative adenovirus for the treatment of breast cancer that allows controlled replication of E1a-deleted adenoviral vectors

The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. To solve this pr oblem, a new generation of tumor-specific, conditionally replicative adenov iruses is being developed. To direct the replication of the virus to breast cancer, me have considered one characteristic present in a great proportio n of these cancers, which is the expression of estrogen receptors (ERs), On the basis of the wild-type adenovirus type 5, we have constructed a condit ionally replicative adenovirus (Ad5ERE2) in which the E1a and E4 promoters have been replaced by a portion of the pS2 promoter containing two estrogen -responsive elements (EREs), This promoter induces transcriptional activati on of the E1a and E4 units in response to estrogens in cells that express t he ERs, Ad5ERE2 is able to kill ER+ human breast cancer cell lines as effic iently as the wild-type virus? but has decreased capacity to affect ER- cel ls. By complementation of the Ela protein in trans, Ad5ERE2 allows restrict ed replication of a conventional E1a-deleted adenoviral vector. When a viru s expressing the proapoptotic gene Bc1-xs (Clarke et nl., Proc. Natl,,Acad, Sci, U,S,A, 1995;92:11024-11028) is used in combination with Ad5ERE2, the ability of both viruses to induce cell death is dramatically increased, and the effect can be modulated by addition of the antiestrogen tamoxifen.