title: Recombinant adenoviruses expressing dominant negative insulin-like growth factor-I receptor demonstrate antitumor effects on lung cancer.
abstract: The continuous growth of tumors depends on the altered regulation of the cell cycle, which is in turn modulated by signals from growth factors and their receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense or dominant negative plasmid transfection can suppress tumorigenicity and induce regression of established tumors. We have constructed two recombinant adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an engineered stop codon at amino acid residue 950, and an adenovirus expressing the soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase domain. Dominant negative inhibition results from competition of the defective receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR. The transduction of both ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF-I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482 effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection of ad-IGF-IR/482 virus showed significant growth suppression in established lung cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have the potential to be effective and practical cancer gene therapy strategies.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, South Korea.
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Seol
authors.forename: Chul-Gyu
authors.initials: CG
authors.lastname: Yoo
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.forename: Sung Koo
authors.initials: SK
authors.lastname: Han
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Shim
authors.forename: Keith
authors.initials: K
authors.lastname: Coffee
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005260:Female; D005799:Genes, Dominant / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013936:Thymidine