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: Choon-Taek Lee, Kyung-Ho Park, Yasushi Adachi, Ja Young Seol, Chul-Gyu Yoo, Young Whan Kim, Sung Koo Han, Young-Soo Shim, Keith Coffee, Mikhail M Dikov, David P Carbone
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 10 Issue 1 Pg. 57-63 (Jan 2003) ISSN: 0929-1903 [Print] England
• PMID: 12489029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• Recombinant Proteins
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Thymidine

Topics

• Adenocarcinoma, Bronchiolo-Alveolar (genetics, metabolism, therapy)
• Adenoviridae (genetics, metabolism)
• Animals
• Carcinoma, Large Cell (genetics, metabolism, therapy)
• Cell Division (drug effects)
• Colony-Forming Units Assay
• Female
• Genes, Dominant (physiology)
• Genetic Therapy (methods)
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Lung Neoplasms (genetics, metabolism, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Receptor, IGF Type 1 (genetics, metabolism)
• Recombinant Proteins (genetics, metabolism)
• Sequence Deletion
• Thymidine (metabolism)
• Transfection
• Tumor Cells, Cultured