Published online before print July 18, 2002, doi: 10.1161/01.ATV.0000030186.66672.36
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2002 American Heart Association, Inc.
Thrombosis |
Analysis of Coagulation Cascade and Endothelial Cell Activation During Inhibition of Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Pathway in Cancer Patients
From the Department of Medical Oncology (B.C.K., H.M.P., K.H.), the Department of Physiology (V.W.M.v.H.), Institute for Cardiovascular Research, and the Department of Clinical Epidemiology and Biostatistics (P.J.K.), VU Medical Center, and the Department of Vascular Medicine and Department of Internal Medicine (M.L., J.C.M.M.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Imperial College (A.K.K.), Hammersmith Hospital, London, UK; and Gaubius Laboratory TNO-PG (V.W.M.v.H.), Leiden, the Netherlands.
Correspondence to H.M. Pinedo, MD, PhD, Department of Medical Oncology, VU Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, Netherlands. E-mail HM.Pinedo{at}vumc.nl
Objective— The angiogenesis inhibitor SU5416 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor-1 and -2. VEGF may be involved in hemostasis by altering the hemostatic properties of endothelial cells. We analyzed the effects of SU5416 on the coagulation cascade and the vessel wall in patients with advanced cancer.
Methods and Results— Markers for thrombin generation, activation of the protein C pathway, fibrinolysis, and endothelial cell activation were measured in patients with renal cell carcinoma, soft tissue sarcoma, or melanoma on days 0, 14, and 28 of treatment with SU5416. Three of 17 sampled patients developed a thromboembolic event in the fifth week of treatment. Markers for thrombin generation and fibrinolysis did not show significant changes. We observed a significant increase in endogenous thrombin potential and of parameters reflecting endothelial cell activation (von Willebrand antigen, soluble tissue factor, and soluble E-selectin) in all patients (P
0.001). In patients experiencing a thromboembolic event, endogenous thrombin potential, soluble tissue factor, and soluble E-selectin increased to a significantly greater extent (P=0.029, P=0.021, and P=0.007, respectively).
Conclusions— VEGF is not only a permeability, proliferation, and migration factor, but it is also a maintenance and protection factor for endothelial cells.
Key Words: vascular endothelial growth factor • endothelial cell function • hemostasis • SU5416
This article has been cited by other articles:
 |
|
 |
|
  Y. Oh, R. S. Herbst, H. Burris, A. Cleverly, L. Musib, M. Lahn, and G. Bepler Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non-Small-Cell Lung Cancer J. Clin. Oncol., March 1, 2008; 26(7): 1135 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Scappaticci, J. R. Skillings, S. N. Holden, H.-P. Gerber, K. Miller, F. Kabbinavar, E. Bergsland, J. Ngai, E. Holmgren, J. Wang, et al. Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab J Natl Cancer Inst, August 15, 2007; 99(16): 1232 - 1239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Schoffski, H. Dumez, P. Clement, A. Hoeben, H. Prenen, P. Wolter, S. Joniau, T. Roskams, and H. Van Poppel Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review Ann. Onc., August 1, 2006; 17(8): 1185 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yano, P. C. Liaw, J. M. Mullington, S.-C. Shih, H. Okada, N. Bodyak, P. M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality J. Exp. Med., June 12, 2006; 203(6): 1447 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Baffert, T. Le, B. Sennino, G. Thurston, C. J. Kuo, D. Hu-Lowe, and D. M. McDonald Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H547 - H559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dowlati, K. Robertson, T. Radivoyevitch, J. Waas, N. P. Ziats, P. Hartman, F. W. Abdul-Karim, J. K. Wasman, J. Jesberger, J. Lewin, et al. Novel Phase I Dose De-escalation Design Trial to Determine the Biological Modulatory Dose of the Antiangiogenic Agent SU5416 Clin. Cancer Res., November 1, 2005; 11(21): 7938 - 7944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Kuenen, G. Giaccone, R. Ruijter, A. Kok, C. Schalkwijk, K. Hoekman, and H. M. Pinedo Dose-Finding Study of the Multitargeted Tyrosine Kinase Inhibitor SU6668 in Patients with Advanced Malignancies Clin. Cancer Res., September 1, 2005; 11(17): 6240 - 6246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Detmar VEGF up-regulates DSCR1: more surprises Blood, July 1, 2004; 104(1): 6 - 7. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Khurana, S. Shafi, J. Martin, and I. Zachary Vascular Endothelial Growth Factor Gene Transfer Inhibits Neointimal Macrophage Accumulation in Hypercholesterolemic Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1074 - 1080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.C. Kuenen, M. Levi, J.C.M. Meijers, V.W.M. van Hinsbergh, J. Berkhof, A.K. Kakkar, K. Hoekman, and H.M. Pinedo Potential Role of Platelets in Endothelial Damage Observed During Treatment With Cisplatin, Gemcitabine, and the Angiogenesis Inhibitor SU5416 J. Clin. Oncol., June 1, 2003; 21(11): 2192 - 2198. [Abstract] [Full Text] [PDF]
|
|