Effect of the Multitargeted Receptor Tyrosine Kinase Inhibitor, ABT-869 [N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea], on Blood Pressure in Conscious Rats and Mice: Reversal with Antihypertensive Agents and Effect on Tumor Growth Inhibition

Autor: Bryan F. Cox, Steven K. Davidsen, Daniel H. Albert, William T. Noonan, Deborah L. Widomski, Paul Tapang, Gary A. Gintant, Pamela H. Franklin, Ryan M. Fryer, Jason A. Segreti, Patricia N. Banfor, Kelly J. Larson
Rok vydání: 2009
Předmět:
Male
medicine.medical_treatment
Angiotensin-Converting Enzyme Inhibitors
Blood Pressure
Mice
SCID
Pharmacology
Benzoates
Receptor tyrosine kinase
Rats
Sprague-Dawley
Mice
chemistry.chemical_compound
Enalapril
Ramipril
Lisinopril
Neoplasms
Telmisartan
Angiotensin Receptor Antagonists
biology
Imidazoles
Protein-Tyrosine Kinases
Calcium Channel Blockers
Vascular endothelial growth factor
Acrylates
Molecular Medicine
Platelet-derived growth factor receptor
medicine.drug
medicine.medical_specialty
Indazoles
Nifedipine
Thiophenes
Internal medicine
medicine
Animals
Humans
Protein Kinase Inhibitors
Antihypertensive Agents
Dose-Response Relationship
Drug
business.industry
Phenylurea Compounds
Growth factor
Xenograft Model Antitumor Assays
Rats
Endocrinology
chemistry
ACE inhibitor
biology.protein
Benzimidazoles
Amlodipine
business
Zdroj: Journal of Pharmacology and Experimental Therapeutics. 329:928-937
ISSN: 1521-0103
0022-3565
DOI: 10.1124/jpet.108.144816
Popis: ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C(20)H(28)N(2)O(5) x C(4)H(4)O(4)) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.
Databáze: OpenAIRE
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