| Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy. | |
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MedLine Citation:
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PMID: 15562829 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-IR reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-IR/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma. |
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Authors:
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Yasushi Adachi; Choon-Taek Lee; David P Carbone |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: Novartis Foundation symposium Volume: 262 ISSN: 1528-2511 ISO Abbreviation: Novartis Found. Symp. Publication Date: 2004 |
Date Detail:
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Created Date: 2004-11-25 Completed Date: 2004-12-21 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9807767 Medline TA: Novartis Found Symp Country: England |
Other Details:
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Languages: eng Pagination: 177-89; discussion 190-2, 265-8 Citation Subset: IM |
Affiliation:
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First Department of Internal Medicine, Sapporo Medical University, Sapporo, 060-8543, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Gene Therapy / methods* Humans Insulin-Like Growth Factor I / antagonists & inhibitors* Neoplasms / therapy* Receptor, IGF Type 1 / antagonists & inhibitors* Signal Transduction |
| Chemical | |
Reg. No./Substance:
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67763-96-6/Insulin-Like Growth Factor I; EC 2.7.10.1/Receptor, IGF Type 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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