The Impact of Pazopanib on the Cardiovascular System
renal cell carcinoma
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Series/Report no.:2017 Fall Undergraduate Research Student Poster Forum. 11th
Background: Pazopanib was FDA-approved in 2009 and has become the first line of treatment for renal cell carcinoma. Pazopanib is a tyrosine kinase inhibitor that slows tumor growth and angiogenesis by its action on vascular endothelial and platelet-derived growth factor receptors. Unfortunately, the efficacy of this drug is limited by its cardiovascular toxicity, including hypertension. Goal: Gain a greater understanding of the mechanism of these side effects in order to: 1) identify patients who are at higher risk; 2) develop strategies to mitigate cardiovascular toxicity; and 3) aid in future drug development. Hypothesis: The hypertensive effects of pazopanib are due to sustained activation of the renin-angiotensin-aldosterone system (RAAS). Methods: Wild type mice were dosed with 30 mg/kg of pazopanib twice daily for 42 days. Cardiac-specific beta-II spectrin knockout mice and flox control mice were dosed with 100 mg/kg once daily for 22 days, and an additional cohort was co-treated with Lisinopril (RAAS inhibitor). Blood pressures were monitored throughout treatment. Electrophysiological studies were conducted on isolated cardiomyocytes. Results: Pazopanib treatment led to an increase in blood pressure in all mice that received pazopanib. After 42 days, precursors to ventricular arrhythmias, such as delayed afterdepolarizations and prolonged action potential duration, were detected in cardiomyocytes. In mice that received 100 mg/kg of pazopanib, lisinopril co-treatment attenuated pazopanib-induced blood pressure rise and enlargement of the heart. Discussion: These results support our hypothesis regarding the involvement of the RAAS pathway, and validate the use of lisinopril for mitigating the hypertensive effects of pazopanib. Notably, the mechanism by which various tyrosine kinase inhibitors lead to hypertension may vary. Conclusion: Lisinopril is effective at attenuating the hypertensive effects of pazopanib, and it is worth determining whether the cardioprotective qualities of lisinopril are dependent upon blood pressure.
Academic Major: Biochemistry
Pelotonia Undergraduate Research Fellowship Program
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