Back to Search
Start Over
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
- Source :
- Clinical Cancer Research. 11:8145-8157
- Publication Year :
- 2005
- Publisher :
- American Association for Cancer Research (AACR), 2005.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....fa1932cc238bc41cb85f5f1bab641e17