Vascular toxicity associated with anti-angiogenic drugs

Abstract

Over the past two decades, the treatment of cancer has been revolutionised by the highly successful introduction of novel molecular targeted therapies and immunotherapies, including small-molecule kinase inhibitors and monoclonal antibodies that target angiogenesis by inhibiting vascular endothelial growth factor (VEGF) signaling pathways. Despite their anti-angiogenic and anti-cancer benefits, the use of VEGF inhibitors (VEGFi) and other tyrosine kinase inhibitors (TKIs) has been hampered by potent vascular toxicities especially hypertension and thromboembolism. Molecular processes underlying VEGFi-induced vascular toxicities still remain unclear but inhibition of endothelial NO synthase (eNOS), reduced nitric oxide (NO) production, oxidative stress, activation of the endothelin system, and rarefaction have been implicated. However, the pathophysiological mechanisms still remain elusive and there is an urgent need to better understand exactly how anti-angiogenic drugs cause hypertension and other cardiovascular diseases (CVDs). This is especially important because VEGFi are increasingly being used in combination with other anti-cancer dugs, such as immunotherapies (immune checkpoint inhibitors (ICIs)), other TKIs, drugs that inhibit epigenetic processes (histone deacetylase (HDAC) inhibitor) and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, which may themselves induce cardiovascular injury. Here, we discuss vascular toxicities associated with TKIs, especially VEGFi, and provide an up-to-date overview on molecular mechanisms underlying VEGFi-induced vascular toxicity and cardiovascular sequelae. We also review the vascular effects of VEGFi when used in combination with other modern anti-cancer drugs.

Incidence and Risk of Hypertension in Cancer Patients Treated With Atezolizumab and Bevacizumab: A Systematic Review and Meta-Analysis

“…More importantly, Hypertension was the most common comorbidity among patients with cancer in a large observational cohort study, with a reported prevalence of 38% ( 28 ). As understanding of targeted therapies improves, there is growing awareness of the importance and detrimental vascular effects of a new generation of antitumor agents ( 29 , 30 ). In this study, we performed a meta-analysis of the incidence and risk of hypertension in cancer patients treated with A-B.…”

Dual sEH/COX-2 Inhibition Using PTUPB—A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity

“…They inhibit the VEGF signaling pathway and neovascularization of tumors, which prevents the blood supply to a tumor, thus, limiting tumor growth ( Grothey and Galanis, 2009 ). Despite their effectiveness as tumor-combating agents, VEGF TKIs can exert a range of adverse effects on cardiovascular and kidney health ( Kappers et al, 2009 ; Perazella, 2012 ; Estrada et al, 2019 ; Neves et al, 2020 ; Dobbin et al, 2021 ). In the present study, sorafenib caused elevation of kidney sEH and COX-2 enzymes.…”

“…Unfortunately, VEGF TKIs come with severe limitations in the form of hypertension, proteinuria, and renal injury ( Humphreys and Atkins, 2009 ; Jhaveri et al, 2011 ; Estrada et al, 2019 ; Versmissen et al, 2019 ; Neves et al, 2020 ). Current guidelines involve monitoring and management of the side effects including blood pressure medications to lower hypertension ( Versmissen et al, 2019 ).…”

Nephrotoxicity of Anti-Angiogenic Therapies

“…These antiangiogenic drugs lead to an imbalance between vasodilator and vasoconstrictor agents, which results in cardiovascular toxic effects (hypertension, pulmonary hypertension, vascular events). Inhibition of eNOS reduces nitric oxide production and thus participates in vascular toxicities [105][106][107].…”