ZD6474, a Novel Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor, Inhibits Tumor Growth of Multiple Nervous System Tumors
| Autor: | David A. Reardon, Roger E. McLendon, Catherine Wheeler, Mark W. Kieran, B.K. Ahmed Rasheed, Darell D. Bigner, Sith Sathornsumetee, Anderson J. Ryan, Jeremy N. Rich, Ling Wang, Stephen T. Keir, Isaiah Dimery, Henry S. Friedman, Michael W. Graner, Arja Kaipainen, Andrea Laforme |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
medicine.drug_class Angiogenesis Mice Nude Vascular endothelial growth inhibitor Tyrosine-kinase inhibitor Central Nervous System Neoplasms Mice chemistry.chemical_compound Piperidines Growth factor receptor Cell Movement Cell Line Tumor Glioma medicine Animals Humans Growth factor receptor inhibitor Epidermal growth factor receptor Phosphorylation Cell Proliferation Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Dose-Response Relationship Drug Neovascularization Pathologic biology medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays ErbB Receptors Vascular endothelial growth factor Ki-67 Antigen Receptors Vascular Endothelial Growth Factor Oncology chemistry Ependymoma Quinazolines Cancer research biology.protein |
| Zdroj: | Clinical Cancer Research. 11:8145-8157 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-05-0319 |
| Popis: | Purpose: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. Experimental Design: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. Results: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. Conclusions: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted. |
| Databáze: | OpenAIRE |
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