The cardiovascular profile and pharmacology of vandetanib and pazopanib

Carter, Joanne (2017) The cardiovascular profile and pharmacology of vandetanib and pazopanib. PhD thesis, University of Nottingham.

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Abstract

Angiogenesis, a process that enables the growth of blood vessels from a pre-existing vasculature and is common to all solid tumours greater than 1 mm3 in size (Gacche and Meshram, 2014). The angiogenic process is heavily promoted by vascular endothelial growth factor (VEGF). Compounds able to inhibit VEGF signalling have been shown to reduce cancer mass (Arjaans et al., 2016). However, VEGF receptor tyrosine kinase inhibitors (RTKIs), a class of anti-VEGF treatment, have been shown to cause cardio-toxicity, with hypertension being a commonly reported, and often severe, side effect (Eskens and Verweij, 2006; Widakowich et al., 2007; Abi Aad et al., 2015). Depending on the nature of the study, the incidence of hypertension in the VEGF RTKI patient population ranges from 23% to 90% (Hamberg et al., 2010; La Vine et al., 2010; Aparicio-Gallego et al., 2011; Bible et al., 2014). Due to the increasing incidence and seriousness of hypertension observed in oncology clinics, it is clear that there are important cardiovascular issues relating to the use of RTKIs, particularly those that target VEGF, that require further exploration. This body of work set out to determine the in vitro potencies of vandetanib, pazopanib, cediranib and sorafenib at VEGFR2, alongside the in vivo cardiovascular haemodynamic and vasoactive profile of vandetanib and pazopanib, two VEGF RTKIs shown to cause hypertension in approximately 32% (Wells et al., 2012) and 33%-40% of the patient population, respectively (Bible et al., 2014).

In NFAT luciferase assays cediranib, sorafenib, pazopanib and vandetanib were shown to inhibit, in a non-competitive fashion, VEGF165 mediated signalling in vitro. In haemodynamic studies, using Doppler flowmetry and telemetry methodologies, both vandetanib and pazopanib caused significant hypertension (P<0.05, in comparision to vehicle). Pazopanib and vandetanib lead to significant vasoconstriction of the mesenteric and hindquarter vascular beds, pazopanib also produced significant vasoconstriction in the renal vascular bed (P<0.05, in comparision to vehicle). None of the variables measured in the haemodynamic studies significantly differed between the 30 mgkg-1day-1 pazopanib and 25 mgkg-1day-1 vandetanib groups. In chronic radio-telemetric studies, vandetanib was shown to cause a significantly greater but more transient increase in mean arterial blood pressure in comparison to pazopanib (P<0.05). Vandetanib was also shown to inhibit VEGF and ACh-mediated vessel dilatation in pressure myography experiments. Finally, vandetanib and pazopanib were shown to induce vasodilatation in the presence of a vasoconstrictor (U46619), a previously unseen finding.

In conclusion, the body of work undertaken here has given novel insight into the ability of non-competative anti-VEGF RTKIs to inhibit VEGF-mediated signalling and vessel dilatation as well as produce direct effect of vessel diameter in the absence of VEGF. It has also produced a validated method of hypertension in a rat model, both in the short and long term. These models have shown that different anti-VEGF RTKIs have different regional haemodynamic and post-treatment hypertensive side effect profiles. These findings are important for understanding the mechanisms behind the therapeutic and non-therapeutic effects of VEGF RTKIs and allow for further research into the signalling mechanism involved in VEGF RKTI-mediated hypertension and the potential therapeutic treatments that could treat this.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Woolard, J.
Bellamy, T.
Keywords: Protein-tyrosine kinase inhibitors, Vascular endothelial growth factor antagonists, Neovascularization inhibitors, Cardiovascular system
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QV Pharmacology
R Medicine > RC Internal medicine
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 40191
Depositing User: Carter, Joanne
Date Deposited: 17 Jul 2017 04:40
Last Modified: 19 Jul 2017 01:13
URI: http://eprints.nottingham.ac.uk/id/eprint/40191

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