Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer.
BACKGROUND
Gastric cancer is the fourth most common malignancy worldwide. Adenoviral vectors (Ads) have been applied for gene therapy of various cancers because of their high transduction efficiency. However, the infectivity of gastrointestinal cancer cells is poor due to the limited expression of the Coxsackie-adenovirus receptor (CAR). In addition, few tumor-specific promoters (TSPs) have been characterized for this type of cancer. To overcome these problems, we proposed TSP-driven conditionally replicating adenoviruses (CRAds) with fiber modification for virotherapy of gastric cancer.


METHODS
We assessed the expression profile of eight TSPs in gastric cancer cell lines and evaluated promising candidates in the context of CRAd cytocidal effect. Next, infectivity enhancement by fiber modifications was analyzed in the gastric cancer cell lines. Finally, we combined the TSP-driven CRAds of choice with the fiber modifications to augment the killing effect.


RESULTS
Out of the eight TSPs, the midkine (MK) and cyclooxygenase-2 (Cox-2M and Cox-2L) promoters showed high transcriptional activity in gastric cancer cells. When these promoters were used in a CRAd context, Cox-2 CRAds elicited the strongest cytocidal effect. The greatest infectivity enhancement was observed with adenoviral vectors displaying 5/3 chimeric fibers. Likewise, Cox-2 CRAds with 5/3 chimeric fibers showed the strongest cytocidal effect in gastric cancer cell lines. Therefore, Cox-2 CRAds with 5/3 chimeric fiber modification showed good selectivity and infectivity in gastric cancer cells to yield enhanced oncolysis.


CONCLUSIONS
Cox-2 CRAds with 5/3 chimeric fiber modification are promising for virotherapy of gastric cancer.
Ono
Hidetaka A
HA
Division of Human Gene Therapy, Department of Medicine, Pathology and Surgery, the Gene Therapy Center, University of Alabama at Birmingham BMR2-410, 901 19th Street South, Birmingham, AL 35294-2172, USA.
Davydova
Julia G
JG
Adachi
Yasuo
Y
Takayama
Koichi
K
Barker
Shannon D
SD
Reynolds
Paul N
PN
Krasnykh
Victor N
VN
Kunisaki
Chikara
C
Shimada
Hiroshi
H
Curiel
David T
DT
Yamamoto
Masato
M
D000256:Adenoviridae / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000235:genetics*; D019886:Gastrin-Releasing Peptide / Q000627:therapeutic use; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000187:drug effects / Q000235:genetics* / Q000627:therapeutic use*; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D000078792:Midkine; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000627:therapeutic use; D011991:Receptors, Virus / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000235:genetics* / Q000628:therapy* / Q000821:virology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016207:Cytokines; D005765:Gastrointestinal Agents; D016023:Integrins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011991:Receptors, Virus; D015842:Serine Proteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000078792:Midkine; D019886:Gastrin-Releasing Peptide; D051546:Cyclooxygenase 2