Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses.
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.
Höti
Naseruddin
N
James Buchanan Brady Urology Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2101, USA.
Li
Ying
Y
Chen
Chien-Lun
CL
Chowdhury
Wasim H
WH
Johns
David C
DC
Xia
Qinghua
Q
Kabul
Arup
A
Hsieh
Jer-Tsong
JT
Berg
Michael
M
Ketner
Gary
G
Lupold
Shawn E
SE
Rodriguez
Ronald
R
D000256:Adenoviridae / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D015513:Oncogene Proteins; D011944:Receptors, Androgen; D011994:Recombinant Proteins