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Polymorphisms in Endothelial Nitric Oxide Synthase ( eNOS ) and Vascular Endothelial Growth Factor ( VEGF ) Predict Sunitinib‐Induced Hypertension
Author(s) -
Eechoute K,
Veldt A A M,
Oosting S,
Kappers M H W,
Wessels J A M,
Gelderblom H,
Guchelaar HJ,
Reyners A K L,
Herpen C M L,
Haanen J B,
Mathijssen R H J,
Boven E
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2012.136
Subject(s) - enos , sunitinib , medicine , blood pressure , vascular endothelial growth factor , endocrinology , vascular endothelial growth factor a , nitric oxide , single nucleotide polymorphism , cardiology , nitric oxide synthase , biology , cancer , vegf receptors , genotype , biochemistry , gene
Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single‐nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A ( VEGFA ), vascular endothelial growth factor receptor ( VEGFR ) ‐2 , endothelin‐1 ( ET‐1 ), and endothelium‐derived nitric oxide synthase ( eNOS ) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA ( P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS ( P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib‐induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months ( P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib‐treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC. Clinical Pharmacology & Therapeutics (2012); 92 4, 503–510. doi: 10.1038/clpt.2012.136