Tetracycline-inducible promoter-based conditionally replicative adenoviruses for the control of viral replication.
The use of conditionally replicative adenoviruses (CRAds) as a promising strategy for cancer gene therapy has been developed to overcome inefficient transduction of solid tumor masses by replication-deficient adenoviruses. Many modifications have been made to CRAds to enlarge tropism, increase selectivity and lytic ability, and improve safety. However, safety is still a concern in the context of future clinical application of CRAds. Particularly, after injection into the body, viral replication cannot be controlled externally. Therefore, we constructed a novel CRAd using a tetracycline-inducible promoter system to realize external pharmacological control of its replication. The effect of this CRAd in vitro was measured at the levels of viral DNA replication, cell death and progeny production. We showed that CRAd replication was tightly controlled by the presence or absence of doxycycline (Dox). Moreover, this system showed a significant gene expression in vivo, in which the viral replication was controlled by the oral administration of Dox. This strategy may help improve the safety of cancer gene therapy.
Zhang
H
H
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Takayama
K
K
Zhang
L
L
Uchino
J
J
Harada
A
A
Harada
T
T
Hisasue
J
J
Nakagaki
N
N
Zhou
C
C
Nakanishi
Y
Y
D000256:Adenoviridae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D013752:Tetracycline / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D011500:Protein Synthesis Inhibitors; D013752:Tetracycline