Oncolytic adenoviral therapy in gallbladder carcinoma.
BACKGROUND
Oncolytic adenoviral therapy is a promising new approach for cancer treatment. The aim of this study was to improve the conditionally replicative adenoviruses (CRAds) for gallbladder cancer therapy by modifying the fiber-knob region for infectivity enhancement and by incorporating tumor-specific promoters (TSPs) for enhanced specificity.


METHODS
For promoter-controlled replication, in vitro efficacy of eight TSPs was investigated in two gallbladder cancer cell lines (NOZ and OCUG-1). Infectivity enhancement was analyzed by two different fiber modifications: Arg-Gly-Asp (RGD) incorporation into the HI loop (RGD modification) and a chimeric construct with a serotype 5 shaft and a serotype 3 knob (5/3 fiber modification). Comparisons were made by infectivity analysis and cytotoxicity assays in vitro, followed by tumor suppressive effects tested in vivo.


RESULTS
Among TSPs, highest potency was exhibited by the cyclooxygenase-2 (COX-2), Midkine, and vascular endothelial growth factor promoters in both cell lines tested. Fiber chimera (Ad5/3Luc1) conferred significant enhancement of Ad infectivity in comparison with unmodified and RGD-modified vectors. COX-2 CRAds demonstrated selective cytocidal effect in gallbladder cancer cells in vitro. COX-2 promoter-based Ad5/3 CRAds showed significantly enhanced tumor-suppressive effect compared with nonreplicative and RGD-modified CRAd vectors in vivo.


CONCLUSIONS
The 5/3 fiber-modified, COX-2 promoter-driven CRAds may prove to be a new agent for the treatment of gallbladder carcinoma.
Tekant
Yaman
Y
Hepatopancreatobiliary Surgery Unit, Department of General Surgery, Istanbul Medical Faculty, Istanbul University, Turkey.
Davydova
Julia
J
Ramirez
Pedro J
PJ
Curiel
David T
DT
Vickers
Selwyn M
SM
Yamamoto
Masato
M
D000256:Adenoviridae; D000818:Animals; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D005260:Female; D005706:Gallbladder Neoplasms / Q000628:therapy*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D014158:Transcription, Genetic; D014779:Virus Replication
D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases