Highly efficient and carcinoma-specific adenoviral replication restricted by the EGP-2 promoter.
Although some successes have been reported using adenoviral vectors for the treatment of cancer, adenoviral cancer gene therapy is still hampered by the lack of sufficient tumor cell killing. To increase the efficiency, adenoviruses have been modified to replicate specifically in tumor tissues by using tumor specific promoters controlling genes essential for adenoviral replication. However, many conditionally replicating adenoviral vectors replicate in one tumor type only, which limits their application. The epithelial glycoprotein-2 (EGP-2) promoter is active in a broad variety of carcinomas, the most common type of cancer. We utilized this promoter to restrict adenoviral replication. In this report we demonstrate that the potency of the replication-competent adenovirus AdEGP-2-E1 to specifically lyse EGP-2 positive cells is comparable to wild-type adenovirus (AdWT). In addition, we show that in vivo AdEGP-2-E1 replicates as efficient as AdWT in EGP-2 positive tumor cells. On the contrary, in EGP-2 negative cell lines as well as in primary human liver samples, the replication was attenuated up to 4-log in comparison to wild-type virus. This report clearly shows the potency of the EGP-2 promoter to mediate highly efficient and specific adenoviral replication for carcinoma gene therapy.
Gommans
W M
WM
Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration, The Netherlands.
McLaughlin
P M J
PM
Schalk
J A C
JA
Groothuis
G M M
GM
Haisma
H J
HJ
Rots
M G
MG
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D004199:Disease Vectors; D000071858:Epithelial Cell Adhesion Molecule; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000235:genetics*
D000954:Antigens, Surface; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule