Restriction of adenoviral replication to the transcriptional intersection of two different promoters for colorectal and pancreatic cancer treatment.
In our current study, we developed oncolytic adenoviruses which preferentially lyse pancreatic and colon cancer cells by replacing viral E1 and/or E4 promoter with the tumor/tissue-specific promoters, cyclooxygenase-2 (COX-2), midkine (MK), or the cell cycle-dependent promoter, E2F1. We generated three sets of recombinant adenoviral vectors. In the first set, only the native E1A promoter was replaced by the COX-2, MK, or E2F1 promoter, respectively. In the second set, the viral E4 promoter was substituted by these heterologous promoters and the viral E1A promoter was substituted by the ubiquitously active cytomegalovirus-IE promoter. In the third set, we substituted the viral E1A and E4 promoters with the COX-2, MK, or E2F1 promoter, respectively. In our system, transcriptional targeting of solitary viral E1A resulted in 50% enhanced restricted vector replication when compared with an unrestricted replication-competent adenovirus. Furthermore, a targeted expression of the viral E1A gene products had a greater effect on restricted adenoviral replication than that of the E4 region. With our vectors, Ad.COX.MK and Ad.MK.COX, using two different heterologous promoters to control E1A and E4 expression, we showed enhanced viral replication specificity when compared with Ad.COX.COX or Ad.MK.MK, respectively. In a s.c. xenograft tumor model, there was no significant difference in the antineoplastic efficacy of the double heterologous promoter-controlled vectors when compared with our unrestricted replication-competent control adenovirus or vectors with only E1A transcriptionally driven by a heterologous promoter.
Hoffmann
Dennis
D
Ruhr-University Bochum, Institute of Microbiology and Hygiene, Department of Molecular and Medical Virology, Building MA, Room 6/40, D-44801 Bochum, Germany.
Wildner
Oliver
O
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D051546:Cyclooxygenase 2 / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D052138:Genes, Neoplasm; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000235:genetics*
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human