1. Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab
- Author
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Silvie Sebastian, Emile E. Voest, Arnold C. Koekman, Astrid A M van der Veldt, Richard J. Honeywell, Marjolein Y.V. Homs, Arjan D. Barendrecht, Naomi M. J. Parr, José J. Koldenhof, Maudy Walraven, Henk L. Dekker, Mark Roest, Suzanne J.A. Korporaal, Henk M.W. Verheul, Medical Oncology, Medical oncology, CCA - Cancer biology and immunology, VU University medical center, and Medical oncology laboratory
- Subjects
Sorafenib ,Blood Platelets ,Male ,Cancer Research ,Platelet Aggregation ,Physiology ,medicine.drug_class ,Clinical Biochemistry ,Angiogenesis Inhibitors ,030204 cardiovascular system & hematology ,Pharmacology ,urologic and male genital diseases ,Tyrosine-kinase inhibitor ,CSK Tyrosine-Protein Kinase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Sunitinib ,Humans ,Platelet ,Original Paper ,business.industry ,Bleeding ,Impaired platelet aggregation ,Fibrinogen binding ,Endothelial Cells ,VEGF ,female genital diseases and pregnancy complications ,Vascular endothelial growth factor ,Bevacizumab ,P-Selectin ,src-Family Kinases ,chemistry ,TKIs ,030220 oncology & carcinogenesis ,Platelet function ,Female ,business ,Ex vivo ,medicine.drug - Abstract
Introduction At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p
- Published
- 2018
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