Journal
CANCER GENE THERAPY
Volume 13, Issue 7, Pages 696-705Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cgt.7700940
Keywords
oncolysis; adenovirus; insulator
Ask authors/readers for more resources
We previously described Ad-Delta 24RGD as an enhanced-infectivity oncolytic adenovirus that targets tumors with an impaired RB pathway. The common alteration of this pathway in cancer eliminates the interaction of pRB with E2F and releases free E2F to activate E2F-responsive promoters, including the E2F-1 promoter. To improve the selectivity towards RB pathway-defective tumors and reduce the toxicity of Ad-Delta 24RGD we aimed to control E1A-Delta 24 expression under the E2F-1 promoter. A polyA signal was inserted upstream of the E2F-1 promoter to stop transcription initiated at the adenovirus ITR and packaging signal. The human myotonic dystropy locus insulator (DM-1) was also located between the E1a enhancers and the E2F-1 promoter to further insulate the promoter. The Ad-Delta 24RGD derivative containing these insulation sequences expressed less E1a-Delta 24 in normal cells and resulted less toxic while maintaining the potent oncolytic activity of the parental virus. These results demonstrate that the human DM-1 inslulator can function in an adenovirus context to maintain heterologous promoter selectivity. The new oncolytic adenovirus presented here may represent a valuable therapeutic option for a broad range of tumors with a deregulated E2F/pRB pathway.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available