Sunitinib uptake inhibits platelet function in cancer patients.

Autor: Sabrkhany S; Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, Maastricht, The Netherlands., Griffioen AW; Angiogenesis Laboratory, Department of Medical Oncology, VU Medical Center, Amsterdam, The Netherlands., Pineda S; Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, Maastricht, The Netherlands., Sanders L; Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, Maastricht, The Netherlands., Mattheij N; Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands., van Geffen JP; Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands., Aarts MJ; Department of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands., Heemskerk JW; Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands., Oude Egbrink MG; Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, Maastricht, The Netherlands., Kuijpers MJ; Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands. Electronic address: Marijke.Kuijpers@maastrichtuniversity.nl.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2016 Oct; Vol. 66, pp. 47-54. Date of Electronic Publication: 2016 Aug 12.
DOI: 10.1016/j.ejca.2016.07.016
Abstrakt: Background: Sunitinib is an oral tyrosine kinase inhibitor used for cancer treatment. Patients treated with sunitinib are at higher bleeding risk. As tyrosine kinases are essential for platelet signalling, the effects of sunitinib on platelet function in vitro and in cancer patients on treatment were investigated.
Patients and Methods: Blood samples were collected from eight healthy volunteers and eight patients diagnosed with metastatic renal cell cancer (RCC) before and 2 weeks on treatment with sunitinib. Platelets from 15 additional healthy individuals were preincubated with sunitinib or vehicle to perform in vitro experiments. Immunofluorescence imaging, western blotting, light transmission aggregometry, whole blood perfusion over collagen, flow cytometry and ELISA were performed.
Results: Confocal microscopy indicated that platelets sequester sunitinib in vitro and in patients. In platelets from healthy controls, tyrosine phosphorylation was inhibited by sunitinib. Also, sunitinib dose dependently reduced collagen- and ADP-induced aggregation, collagen-dependent thrombus formation and collagen-induced secretion of platelet-derived growth factor and β-thromboglobulin. In blood from RCC patients before treatment, thrombus formation and procoagulant activity under flow were 47% and 80% higher than in healthy controls. After 14 d of sunitinib treatment, platelet count was moderately, but significantly decreased (from 243 to 144 × 10(9)/l). At the same time, collagen-induced platelet aggregation as well as thrombus formation and phosphatidylserine exposure under flow were significantly reduced (by 45%, 16% and 61%, respectively).
Conclusions: Sunitinib uptake by platelets inhibits collagen receptor-induced aggregation and thrombus formation via reduction of protein tyrosine phosphorylation and α-granule secretion. This dysfunction may contribute to the higher bleeding tendency observed in sunitinib-treated patients.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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