Inhibition of the type I insulin-like growth factor receptor expression and signaling: Novel strategies for antimetastatic therapy

The receptor for the type 1 insulin-like growth factor (IGF-1R) plays a critical role in the acquisition of the malignant phenotype. Using a highly metastatic murine lung carcinoma model, it was demonstrated that this receptor regulates several cellular functions that can impact on the metastatic po...

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Bibliographic Details
Published in:Biochemical pharmacology 2000-10, Vol.60 (8), p.1101-1107
Main Authors: Brodt, Pnina, Samani, Amir, Navab, Roya
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Biological and medical sciences
cancer metastasis
Cell physiology
Disease Models, Animal
Fundamental and applied biological sciences. Psychology
IGF-I receptor
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Mice
Molecular and cellular biology
Neoplasm Metastasis - physiopathology
Receptor, IGF Type 1 - antagonists & inhibitors
Receptor, IGF Type 1 - biosynthesis
Receptor, IGF Type 1 - physiology
Signal transduction
Signal Transduction - physiology
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Summary:The receptor for the type 1 insulin-like growth factor (IGF-1R) plays a critical role in the acquisition of the malignant phenotype. Using a highly metastatic murine lung carcinoma model, it was demonstrated that this receptor regulates several cellular functions that can impact on the metastatic potential of the cells, including cellular proliferation, anchorage-independent growth, cell migration, and invasion. The tumor model was used to develop several strategies for altering receptor expression and function as means of abrogating the metastatic potential of the cells. They include stable expression in the tumor cells of IGF-1R antisense RNA and dominant negative receptor mutants in which tyrosines in the kinase domain were substituted with phenylalanine. In addition, a novel strategy was used based on altering post ligand-binding receptor turnover. This led to inhibition of receptor re-expression and signaling and resulted in increased tumor cell apoptosis. When combined with the development of viral vectors designed to deliver genetic information with high efficiency, these strategies could form the basis for development of highly specific, antimetastatic therapy in tumors with known IGF-IR involvement.
ISSN:0006-2952
1873-2968
DOI:10.1016/S0006-2952(00)00422-6