Tumor-specific gene expression in carcinoembryonic antigen--producing gastric cancer cells using adenovirus vectors.
OBJECTIVE
An increase of carcinoembryonic antigen (CEA) expression is noted in about 40% of patients with gastric cancer. Adenovirus-mediated gene therapy using the CEA promoter was investigated as a way to specifically target human CEA-producing gastric tumors.


METHODS
Recombinant adenovirus vectors carrying a CEA promoter linked to the lacZ gene (AdCEA lacZ) or the cytosine deaminase gene (AdCEA-CD) were constructed. After infection with these vectors, CEA-producing (MKN45 and MKN28) and non-CEA-producing (MKN1) gastric cancer cells were analyzed for transgene expression and sensitivity to 5-fluorocytosine.


RESULTS
The lacZ gene was expressed selectively in CEA-producing AdCEA-lacZ-infected cells in vitro and in vivo. Transduction of the vector containing the CEA-regulated cytosine deaminase gene (AdCEA-CD) resulted in extraordinary sensitivity of MKN45 and MKN28 cells to 5-fluorocytosine. This effect was not observed in MKN1 cells. Moreover, AdCEA-CD-infected MKN45 cells showed a profound in vitro neighbor cell killing effect in the presence of 5-fluorocytosine. This effect was attributed to the diffusion of 5-fluorouracil, resulting from conversion of 5-fluorocytosine to 5-fluorouracil by the cytosine deaminase-expressing cells.


CONCLUSIONS
The results of this study suggest that use of a CEA promoter in an adenovirus vector could confer selective expression of the cytosine deaminase gene in CEA-producing gastric cancer cells, rendering the transduced cells susceptible to 5 fluorocytosine. This system may be useful in gene therapy that targets CEA-producing gastric carcinomas.
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
K H
KH
Lan
F
F
Kanai
Y
Y
Shiratori
S
S
Okabe
Y
Y
Yoshida
H
H
Wakimoto
H
H
Hamada
T
T
Tanaka
M
M
Ohashi
M
M
Omata
D000256:Adenoviridae / Q000235:genetics*; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics*; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009700:Nucleoside Deaminases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000378:metabolism / Q000628:therapy*; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil