Androgen receptor attenuation of Ad5 replication: Implications for the development of conditionally replication competent adenoviruses

Naseruddin Höti, Ying Li, Chien Lun Chen, Wasim H. Chowdhury, David C. Johns, Qinghua Xia, Arup Kabul, Jer Tsong Hsieh, Michael Berg, Gary Ketner, Shawn E. Lupold, Ronald Rodriguez

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Conditionally replication competent adenoviruses (CRAds) represent one of the most intensely studied gene therapy strategies for a variety of malignancies, including prostate cancer. These viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We report here that E1A inhibits androgen receptor (AR) target gene induction and, correspondingly, activated AR inhibits adenoviral replication. This mutual inhibition appears to be an indirect effect, possibly through competition for shared transcriptional co-activators. The net effect is that the oncolytic effect of prostate-specific CRAds is attenuated by these interactions. Fusion of the E1A to AR ameliorates this inhibition, while enhancing specificity. These findings have significant implications in the development of prostate-specific CRAd therapies.

Original languageEnglish (US)
Pages (from-to)1495-1503
Number of pages9
JournalMolecular Therapy
Volume15
Issue number8
DOIs
StatePublished - Aug 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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