Adenovirus-mediated prodrug gene therapy for carcinoembryonic antigen-producing human gastric carcinoma cells in vitro.
We analyzed the ability of a recombinant replication-defective adenovirus vector with the carcinoembryonic antigen (CEA) promotor to transfer the thymidine kinase gene of herpes simplex virus (HSVtk) into gastric cancer cells to confer sensitivity to ganciclovir (GCV). CEA-producing gastric cancer cell lines (MKN28 and MKN45), a CEA-nonproducing gastric cancer cell line (MKN1), and a human uterine cervical cancer cell line (HeLa) were infected with a recombinant adenovirus carrying lacZ reporter gene coupled to the CEA promoter (AdCEAlacZ). The efficiency of AdCEAlacZ-mediated gene transfer was correlated with the amount of CEA produced by each cell line. Furthermore, the 50% growth inhibitory concentrations (IC50) of GCV were 21 and 5.8 microm for MKN28 and MKN45, respectively, when infected with a recombinant adenovirus carrying the HSVtk gene coupled to the CEA promoter (AdCEAtk). However, MKN1 and HeLa cells infected with AdCEAtk remained resistant to GCV (IC50 > 300 microm of GCV). In addition, a bystander killing effect was demonstrated against MKN45 cells when only 20% of AdCEAtk-infected cells were mixed with uninfected cells. These data indicate the potential for targeted gene therapy using the cell type-specific promotor of the CEA gene against gastric cancers that produce CEA.
Tanaka
T
T
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Kanai
F
F
Okabe
S
S
Yoshida
Y
Y
Wakimoto
H
H
Hamada
H
H
Shiratori
Y
Y
Lan
K
K
Ishitobi
M
M
Omata
M
M
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis*; D003673:Defective Viruses / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D002272:Carcinoembryonic Antigen; D013937:Thymidine Kinase; D015774:Ganciclovir