ZD6474 - a novel inhibitor of VEGFR and EGFR tyrosine kinase activity

Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in...

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Bibliographic Details
Published in:British journal of cancer 2005-06, Vol.92 (S1), p.S6-S13
Main Authors: Ryan, A J, Wedge, S R
Format: Article
Language:English
Subjects:
Administration, Oral
Angiogenesis
Biological Availability
Biomedical and Life Sciences
Biomedicine
Blood vessels
Cancer Research
Cell growth
Cell Survival
Drug Administration Schedule
Drug Resistance
Epidemiology
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - genetics
Humans
Kinases
Ligands
Medical prognosis
Medical research
Molecular Medicine
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - physiopathology
Neovascularization, Pathologic
Oncology
Original
original-article
Permeability
Piperidines - administration & dosage
Piperidines - pharmacology
Piperidines - therapeutic use
Quinazolines - administration & dosage
Quinazolines - pharmacology
Quinazolines - therapeutic use
Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors
Receptors, Vascular Endothelial Growth Factor - genetics
Signal Transduction
Tumors
Vascular endothelial growth factor
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Summary:Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in stimulating neovascular growth and survival. ZD6474 is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumour-induced angiogenesis. Consistent with inhibition of angiogenesis, once-daily oral dosing of ZD6474 produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, ZD6474 also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. This may be particularly relevant in tumours with a dependency upon EGFR signalling, for example in certain tumours harbouring activating mutations in EGFR. RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6602603