Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo.
Pharmacological control is a desirable safety feature of oncolytic adenoviruses (oAdV). It has recently been shown that oAdV replication may be controlled by drug-dependent transcriptional regulation of E1A expression. Here, we present a novel concept that relies on tamoxifen-dependent regulation of E1A activity through functional linkage to the mutated hormone-binding domain of the murine estrogen receptor (Mer). Four different E1A-Mer chimeras (ME, EM, E(DeltaNLS)M, MEM) were constructed and inserted into the adenoviral genome under control of a lung-specific surfactant protein B promoter. The highest degree of regulation in vitro was seen for the corresponding oAdVs Ad.E(DeltaNLS)M and Ad.MEM, which exhibited an up to 100-fold higher oAdV replication in the presence as compared with the absence of 4-OH-tamoxifen. Moreover, destruction of nontarget cells was six- and 13-fold reduced for Ad.E(DeltaNLS)M and Ad.MEM, respectively, as compared with Ad.E. Further investigations supported tamoxifen-dependent regulation of Ad.E(DeltaNLS)M and Ad.MEM in vivo. Induction of Ad.E(DeltaNLS)M inhibited growth of H441 lung tumors as efficient as a control oAdV expressing E1A. E(DeltaNLS)M and the MEM chimeras can be easily inserted into a single vector genome, which extends their application to existing oAdVs and strongly facilitates in vivo application.
Sipo
I
I
Department of Cardiology and Pneumology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Germany.
Wang
X
X
Hurtado Picó
A
A
Suckau
L
L
Weger
S
S
Poller
W
W
Fechner
H
H
D000230:Adenocarcinoma / Q000628:therapy* / Q000821:virology; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D003588:Cytopathogenic Effect, Viral; D005260:Female; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000627:therapeutic use*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D017500:Adenovirus E1A Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D013629:Tamoxifen; C016601:afimoxifene