An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells.
The promoter for human telomerase reverse transcriptase (hTERTp) is preferentially active in malignant cells. It was recently used to control the expression of the adenoviral E1A gene for the development of oncolytic adenoviruses. To ensure maximal repression in normal cells, the inclusion of additional E-boxes in the proximal region of the core promoter was described. We found that the transcriptional activity of this artificial sequence (T-255-4DEB) is minimal in normal cells, but it is also reduced in all the cancer cell lines tested. The cancer specificity of a new oncolytic adenovirus based in this promoter (AdTE1) was evaluated by direct comparison with wild-type adenovirus type 5 (AdWT) in vitro and in vivo. In all the parameters tested, AdTE1 was attenuated in normal cells, but the efficacy in cancer cells showed a parallel reduction, suggesting a lack of specificity. However, the cytotoxicity of AdTE1 was repressed in senescent cells compared to AdWT. Therefore, we conclude that AdTE1 is preferentially attenuated only in cells that are permanently devoid of telomerase expression such as senescent cells. Further modifications in the telomerase-based promoters should be introduced in order to combine maximal attenuation of oncolytic adenoviruses in normal tissues and enhanced activity in tumors.
Padua University Surgical and Gastroenterological Sciences, Padua, 35128, Italy.
S
S
Bortolanza
C
C
Qian
M G
MG
Kramer
C
C
Gomar
J
J
Prieto
F
F
Farinati
R
R
Hernandez-Alcoceba
D000256:Adenoviridae; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D019098:Telomerase