Thromboembolic Events in Patients Treated with Anti-Angiogenic Drugs

被引:46
作者
Ferroni, Patrizia [1 ]
Formica, Vincenzo [2 ]
Roselli, Mario [2 ]
Guadagni, Fiorella [1 ]
机构
[1] IRCCS San Raffaele Pisana, Dept Lab Med & Adv Biotechnol, I-00163 Rome, Italy
[2] Univ Roma Tor Vergata, Dept Internal Med, Policlin Tor Vergata, I-00133 Rome, Italy
关键词
Vascular endothelial growth factor; oxidant stress; nitric oxide; bevacizumab; endothelial dysfunction; haemostatic activation; ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; NITRIC-OXIDE SYNTHASE; METASTATIC COLORECTAL-CANCER; PROTEIN-KINASE-C; STIMULATES TYROSINE PHOSPHORYLATION; VIVO PLATELET ACTIVATION; FACTOR VEGF; HYDROGEN-PEROXIDE; PHASE-II;
D O I
10.2174/157016110790226660
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Induction of neo-angiogenesis is a fundamental step in many pathological conditions. The therapeutic value of inhibiting angiogenesis is an interesting area of research in oncology, with vascular endothelial growth factor (VEGF) being the most suitable anti-angiogenic target. In the last decade a number of anti-VEGF drugs have demonstrated, especially in combination with standard chemotherapy, clinical efficacy in the treatment of different solid tumor types. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a permeability, proliferation, and migration factor, is also a maintenance and protection factor for endothelial cells, being capable of regulating multiple biological functions, i.e. the production of vasoactive mediators and the expression of components of the thrombolytic and coagulation pathways. Consequently, the disturbance of vascular homeostasis by blocking VEGF may lead to endothelial dysfunction and adverse vascular effects, such as venous and arterial thromboembolic events. In preclinical models angiogenesis and the increased expression of VEGF has been associated to altered expression of proinflammatory genes. These genes may be regulated in a biphasic manner, and it is possible that anti-VEGF therapy may disrupt a negative feedback loop that leads to potential in situ thrombus formation. Accordingly, combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was recently associated with an increased risk of thromboembolism. The present review considers the biological mechanisms and clinical impact of thromboembolic complications during anti-angiogenic treatments in cancer patients.
引用
收藏
页码:102 / 113
页数:12
相关论文
共 122 条
[81]   Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma [J].
Palumbo, A. ;
Rajkumar, S. V. ;
Dimopoulos, M. A. ;
Richardson, P. G. ;
Miguel, J. San ;
Barlogie, B. ;
Harousseau, J. ;
Zonder, J. A. ;
Cavo, M. ;
Zangari, M. ;
Attal, M. ;
Belch, A. ;
Knop, S. ;
Joshua, D. ;
Sezer, O. ;
Ludwig, H. ;
Vesole, D. ;
Blade, J. ;
Kyle, R. ;
Westin, J. ;
Weber, D. ;
Bringhen, S. ;
Niesvizky, R. ;
Waage, A. ;
von Lilienfeld-Toal, M. ;
Lonial, S. ;
Morgan, G. J. ;
Orlowski, R. Z. ;
Shimizu, K. ;
Anderson, K. C. ;
Boccadoro, M. ;
Durie, B. G. ;
Sonneveld, P. ;
Hussein, M. A. .
LEUKEMIA, 2008, 22 (02) :414-423
[82]   Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells [J].
Papapetropoulos, A ;
García-Cardeña, G ;
Madri, JA ;
Sessa, WC .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (12) :3131-3139
[83]   Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium [J].
Parenti, A ;
Morbidelli, L ;
Cui, XL ;
Douglas, JG ;
Hood, JD ;
Granger, HJ ;
Ledda, F ;
Ziche, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (07) :4220-4226
[84]   Extracellular signal-regulated protein kinase Jun kinase cross-talk underlies vascular endothelial cell growth factor-induced endothelial cell proliferation [J].
Pedram, A ;
Razandi, M ;
Levin, ER .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (41) :26722-26728
[85]   VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) INDUCES PLASMINOGEN ACTIVATORS AND PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN MICROVASCULAR ENDOTHELIAL-CELLS [J].
PEPPER, MS ;
FERRARA, N ;
ORCI, L ;
MONTESANO, R .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 181 (02) :902-906
[86]   Effects on platelet function of combination etoposide and carboplatin chemotherapy in pediatric oncology patients [J].
Pignatelli, P ;
Properzi, E ;
Pisani, M ;
Clerico, A ;
Schiavetti, A ;
Lenti, L ;
Pulcinelli, FM ;
Ferroni, P ;
Gazzaniga, PP .
PLATELETS, 1998, 9 (05) :309-314
[87]   VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase [J].
Qi, JH ;
Claesson-Welsh, L .
EXPERIMENTAL CELL RESEARCH, 2001, 263 (01) :173-182
[88]   Hydrogen peroxide formation and actin filament reorganization by Cdc42 are essential for ethanol-induced in vitro angiogenesis [J].
Qian, Y ;
Luo, J ;
Leonard, SS ;
Harris, GK ;
Millecchia, L ;
Flynn, DC ;
Shi, XL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (18) :16189-16197
[89]  
Qu H., 1995, Journal of Histochemistry and Cytochemistry, V43, P381
[90]   Human prothrombin fragment 1 and 2 inhibit bFGF-induced BCE cell growth [J].
Rhim, TY ;
Park, CS ;
Kim, E ;
Kim, SS .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 252 (02) :513-516