Recombinant adenoviruses expressing dominant negative insulin-like growth factor-I receptor demonstrate antitumor effects on lung cancer

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 α subunit and a defective β

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.

This work is supported by Grants from the Medical Research Center from Seoul National University (2000) to C-T Lee and DP Carbone (NCI 5P30CA68485).

Department of Internal Medicine, Seoul National University College of Medicine, Lung Institute of Medical Research Center, Seoul National University, Gene Therapy Laboratory of Clinical

Research Institute, Seoul National University Hospital, Seoul, South Korea

Choon-Taek Lee, Kyung-Ho Park, Ja Young Seol, Chul-Gyu Yoo, Young Whan Kim, Sung Koo Han & Young-Soo Shim

Vanderbilt-Ingram Cancer Center and Department of Medicine, Vanderbilt University, Nashville, 37232-6838, Tennessee, USA

Yasushi Adachi, Keith Coffee, Mikhail M Dikov & David P Carbone

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