A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses.
The E2F-1 promoter has been used to confer tumor-selective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-Delta24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The Delta24 deletion avoids a loop of E2F-mediated self-activation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.
Rojas
J J
JJ
Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
Cascallo
M
M
Guedan
S
S
Gros
A
A
Martinez-Quintanilla
J
J
Hemminki
A
A
Alemany
R
R
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human