In vivo transfer of bacterial marker genes results in differing levels of gene expression and tumor progression in immunocompetent and immunodeficient mice.
To optimize gene delivery for the treatment of malignant mesothelioma, expression of the beta-galactosidase marker gene was examined in a murine model of intraperitoneal malignant mesothelioma. The beta-galactosidase gene was delivered to the peritoneal cavity of tumor-bearing mice by various plasmid-liposome complexes or by replication-incompetent retrovirus, used alone or complexed to liposomes. In tumor samples from immunodeficient nude mice, moderate levels of gene expression were achieved by liposome-complexed plasmids. Retroviral gene delivery was more effective, and was increased nearly 10-fold by complexing the retrovirus to liposomes. In contrast, in tumor samples from immunocompetent CBA mice treated with the same vectors, no marker gene expression was detected. In immunodeficient mice, tumor growth was not affected by beta-galactosidase gene transfer. However, immunocompetent mice showed a significant decrease in tumor size and increase in survival time after beta-galactosidase delivery. Induction of cytotoxic T cells capable of lysing beta-Gal-transfected tumor cells suggests that tumor cells transduced with the bacterial beta-galactosidase gene may be eliminated in immunocompetent hosts. Our findings also indicate that plasmid-liposome complexes, which achieve a low level of gene expression, and retrovirus-liposome complexes, which result in nearly 100 times higher levels of gene expression in tumor cells in vivo, are similarly effective in inducing an antitumor immune response.
Lukacs
K V
KV
National Heart and Lung Institute at Imperial College, London, UK. k.lukacs@ic.ac.uk
Porter
C D
CD
Pardo
O E
OE
Oakley
R E
RE
Steel
R M
RM
Judd
D V
DV
Browning
J E
JE
Geddes
D M
DM
Alton
E W
EW
D000818:Animals; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D018014:Gene Transfer Techniques; D005798:Genes, Bacterial; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D008081:Liposomes; D008654:Mesothelioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D008081:Liposomes; D001616:beta-Galactosidase