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.
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.
Franklin
Pamela H
PH
Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA.
Banfor
Patricia N
PN
Tapang
Paul
P
Segreti
Jason A
JA
Widomski
Deborah L
DL
Larson
Kelly J
KJ
Noonan
William T
WT
Gintant
Gary A
GA
Davidsen
Steven K
SK
Albert
Daniel H
DH
Fryer
Ryan M
RM
Cox
Bryan F
BF
D000179:Acrylates / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009543:Nifedipine / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077333:Telmisartan; D013876:Thiophenes / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D002121:Calcium Channel Blockers; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D017311:Amlodipine; C068373:eprosartan; D004656:Enalapril; C513486:linifanib; D017706:Lisinopril; D011505:Protein-Tyrosine Kinases; D009543:Nifedipine; D017257:Ramipril; D000077333:Telmisartan