title: Alterations in tumorigenicity of embryonal carcinoma cells by IGF-I triple-helix induced changes in immunogenicity and apoptosis.
abstract: IGF-I antisense gene therapy has been applied successfully to animal models of glioma, hepatoma and teratocarcinoma. The antisense strategy has shown that tumor cells transfected with vectors encoding IGF-I antisense RNA lose tumorigenicity, become immunogenic and are associated with tumor specific immune response involving CD8+ lymphocytes. An IGF-I triple helix approach to gene therapy for glioma was recently described. The approach we have taken is to establish parameters of change using the IGF-I triple helix strategy. PCC-3 embryonal carcinoma cells derived from murine teratocarcinoma which express IGF-I were used as a model. The cells were transfected with vector which encodes an oligoribonucleotide that forms RNA-IGF-I DNA triple-helix structure. The triple-helix stops the production of IGF-I. Cells transfected in this manner underwent changes in phenotype and an increase in MHC-I and B-7 cell surface molecules. They also showed enhancement in the production of apoptotic cells (60-70%). The "triple helix" transfected cells lost the ability to induce tumor when injected subcutaneously in syngeneic 129 Sv mice. When co-transfected in vitro with expression vectors encoding both MHC-I and B-7 cDNA in antisense orientation, the "triple-helix" transfected cells were down-regulated in expression of MHC-I and B-7 and the number of apoptotic cells was significantly decreased. Injection of the doubly co-transfected cells into 129 Sv mice was associated with induction of teratocarcinoma. Comparison between antisense and triple-helix transfected cells strategies showed similar immunogenic and apoptotic changes. The findings suggest that triple-helix technology may offer a new clinical approach to treatement of tumors expressing IGF-I.
authors.affiliation: LabNeurologie, INSERM/Université Paris VII, H pital Robert Debré, France.
authors.forename: A
authors.initials: A
authors.lastname: Ly
authors.forename: J C
authors.initials: JC
authors.lastname: Francois
authors.forename: L C
authors.initials: LC
authors.lastname: Upegui-Gonzalez
authors.forename: B
authors.initials: B
authors.lastname: Swiercz
authors.forename: C
authors.initials: C
authors.lastname: Bedel
authors.forename: H T
authors.initials: HT
authors.lastname: Duc
authors.forename: D
authors.initials: D
authors.lastname: Bout
authors.forename: J
authors.initials: J
authors.lastname: Trojan
mesh_terms: D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D018236:Carcinoma, Embryonal / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D004247:DNA; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D016372:RNA, Antisense / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018122:B7-1 Antigen; D015395:Histocompatibility Antigens Class I; D016372:RNA, Antisense; C051802:triplex DNA; D007334:Insulin-Like Growth Factor I; D004247:DNA