Abstract
Novel antiangiogenic cancer therapies, particularly agents that block vascular endothelial
growth factor (VEGF) signalling, have improved outcomes in patients with cancers and
are now used as first-line therapies for some tumours. However, with VEGF inhibitors
(VEGFIs) are new complications, particularly hypertension. VEGFI-induced hypertension
is a dose-dependent phenomenon due to on-target effects rather than off-target effects.
Increased blood pressure occurs in almost 100% of patients who take VEGFIs, with a
subset who develop severe hypertension. Molecular mechanisms underlying VEGFI-induced
hypertension are unclear, but endothelial dysfunction and increased vascular resistance,
due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1
(ET-1) upregulation, oxidative stress, and rarefaction have been implicated. Treatment
of hypertension should be aimed at reducing the risk of short-term morbidity associated
with hypertension while maintaining effective dosing of antiangiogenic therapy for
optimal cancer treatment. Although specific guidelines are not yet available for the
management of VEGFI-induced hypertension, angiotensin-converting enzyme inhibitors
and dihydropyridine calcium channel blockers are commonly used. Severe hypertension
might require reduction of VEGFI dosing, or in some cases, interruption of treatment.
As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs,
the burden of hypertension toxicity will increase. This will be further compounded
as the use of antiangiogenic drugs broadens to include older patients and those with
pre-existing cardiovascular disease. Here we focus on VEGF as a target for antiangiogenesis
and how this affects increased blood pressure. Putative mechanisms underlying VEGFI-induced
hypertension are highlighted and therapeutic strategies to manage such hypertension
are discussed.
Résumé
Les nouveaux traitements antiangiogéniques utilisés contre le cancer, particulièrement
les agents qui bloquent la signalisation du facteur de croissance endothéliale vasculaire
(FCEV), ont amélioré les résultats chez les patients souffrant de cancer et sont maintenant
utilisés comme traitement de première intention de certaines tumeurs. Cependant, les
inhibiteurs du FCEV (IFCEV) présentent de nouvelles complications, particulièrement
l’hypertension artérielle. L’hypertension induite par les IFCEV est un phénomène dose-dépendant
dû aux effets ciblés plutôt qu’aux effets non ciblés. L’augmentation de la pression
artérielle apparaît chez presque 100 % des patients qui prennent les IFCEV, avec un
sous-ensemble qui développe une hypertension grave. Les mécanismes moléculaires sous-jacents
à l’hypertension induite par les IFCEV demeurent incertains, mais la dysfonction endothéliale
et l’augmentation de la résistance vasculaire en raison de l’altération de la signalisation
de l’oxyde nitrique, la réduction de la production de prostacycline, la régulation
à la hausse de l’ET-1, le stress oxydatif et la raréfaction ont été impliqués. Le
traitement de l’hypertension devrait avoir pour but de réduire le risque de morbidité
à court terme associée à l’hypertension tout en maintenant le traitement antiangiogénique
à un dosage efficace pour optimiser le traitement contre le cancer. Bien que des lignes
directrices spécifiques à la prise en charge de l’hypertension induite par les IFCEV
ne soient pas encore disponibles, les inhibiteurs de l’enzyme de conversion de l’angiotensine
et les bloqueurs des canaux calciques de la classe des dihydropyridines sont fréquemment
utilisés. L’hypertension grave exigerait la réduction du dosage des IFCEV, ou dans
certains cas, l’interruption du traitement. Puisque des IFCEV plus puissants sont
élaborés et puisque plus de patients atteints de cancer sont traités par les IFCEV,
le fardeau de la toxicité liée à l’hypertension augmentera. Ce fardeau sera davantage
aggravé puisque l’utilisation des médicaments antiangiogéniques s’étendra aux patients
âgés et à ceux qui sont atteints d’une maladie cardiovasculaire. Ici, nous mettons
l’accent sur les FCEV en tant que cible de l’antiangiogenèse et sur la manière qu’ils
influencent l’augmentation de la pression artérielle. Les mécanismes présumés sous-jacents
à l’hypertension induite par les IFCEV sont soulignés, et les stratégies thérapeutiques
pour prendre en charge cette hypertension sont discutées.
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Article info
Publication history
Published online: February 27, 2014
Accepted:
February 20,
2014
Received:
February 20,
2014
Footnotes
See page 540 for disclosure information.
Identification
Copyright
© 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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Access this article on ScienceDirectLinked Article
- Hypertension Due to Antiangiogenic Cancer Therapy With VEGF Inhibitors: Is Autonomic Nervous System Toxicity Another Possible Mechanism?Canadian Journal of CardiologyVol. 30Issue 12
- PreviewWe read with interest the review article by Small et al., on the subject of vascular endothelial growth factor (VEGF) inhibitor-induced hypertension. This is an important, emerging cross-disciplinary area and the review was timely. In their article, the authors outline several potential mechanisms for VEGF inhibitor-induced hypertension, including downregulation of nitric oxide species, decreases in prostacyclin signalling, increases in generation of endothelin, and bioavailability of reactive oxygen species, rarefaction, renal dysfunction, and volume overload.
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