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

Hum Gene Ther. 2000 Sep 20;11(14):2009-24. doi: 10.1089/10430340050143435.


The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. To direct the replication of the virus to breast cancer, we have considered one characteristic present in a great proportion 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type 5, we have constructed a conditionally replicative adenovirus (Ad5ERE2) in which the E1a and E4 promoters have been replaced by a portion of the pS2 promoter containing two estrogen-responsive elements (EREs).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 activation of the E1a and E4 units in response to estrogens in cells that express the ERs. Ad5ERE2 is able to kill ER(+) human breast cancer cell lines as efficiently as the wild-type virus, but has decreased capacity to affect ER(-) cells. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. When a virus expressing the proapoptotic gene Bc1-xs (Clarke et al., 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenovirus E1A Proteins / genetics*
  • Adenovirus E4 Proteins / genetics
  • Animals
  • Breast Neoplasms / therapy*
  • Cell Death
  • Estrogens / genetics
  • Estrogens / pharmacology
  • Female
  • Gene Deletion
  • Genes, Reporter
  • Genetic Therapy / methods*
  • Genetic Vectors*
  • Humans
  • Luciferases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Genetic
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Receptors, Estrogen / genetics
  • Response Elements / genetics
  • Tamoxifen / pharmacology
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured


  • Adenovirus E1A Proteins
  • Adenovirus E4 Proteins
  • Estrogens
  • Receptors, Estrogen
  • Tamoxifen
  • Luciferases