Chancen und Risiken der Anti-VEGF-Therapie

F. Ziemssen; P. Heiduschka; S. Peters; S. Grisanti; U. Schraermeyer

doi:10.1055/s-2008-1027487

Klinische Monatsblätter für Augenheilkunde, Table of Contents

Klin Monbl Augenheilkd 2008; 225(9): 770-778
DOI: 10.1055/s-2008-1027487

Übersicht

Chancen und Risiken der Anti-VEGF-Therapie

Chances and Risks of Anti-VEGF TherapyF. Ziemssen¹ , P. Heiduschka² , S. Peters¹ , S. Grisanti³ , U. Schraermeyer²

¹Eberhard-Karl-Universität Tübingen, Department für Augenheilkunde
²Sektion für experimentelle vitreoretinale Chirurgie, Department für Augenheilkunde, Tübingen
³Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Augenheilkunde

Abstract

Zusammenfassung

Der vascular endothelial growth factor (VEGF) besitzt eine Schlüsselrolle für die Regulation der Angiogenese. Weil der pluripotente Faktor aber auch physiologische Abläufe wie Hämodynamik, Hämatopoese, Immunabwehr, Hormonfreisetzung und Wundheilung beeinflusst, müssen mögliche Interaktionen einer medikamentösen Hemmung berücksichtigt werden. Die Erfahrungen mit der höher dosierten, intravenösen Gabe des Vollantikörpers Bevacizumab (Avastin®) haben das Augenmerk auf mögliche Nebenwirkungen durch eine vollständige VEGF-Blockade gelenkt. Bisherige Daten deuten darauf hin, dass selbst nach intravitrealer Injektion eine systemische Exposition erreicht wird, die zu messbaren Effekten führen kann. Eine Veränderung relevanter Kreislaufparameter könnte eine direkte Beeinflussung der Morbidität bewirken. Obwohl vorerst keine drastischen Auswirkungen beobachtet wurden, lassen die bisherigen Studien keine sichere Beurteilung von Signifikanz und Relevanz zu. Eine VEGF-Blockade kann den Tonus und die Autoregulation der Netzhautgefäße verändern. Die physiologische Fenestrierung der choroidalen Aderhautgefäße zeigte sich im Tiermodell signifikant reduziert. Mögliche Auswirkungen auf die lokale Sauerstoffversorgung in ischämischen Netzhautarealen (Gefäßverschlüsse) können für den klinischen Alltag nicht ausgeschlossen werden. In der Therapie retinaler Neovaskularisationen versprechen die VEGF-Inhibitoren allerdings gegenüber destruktiven Therapieverfahren (Laserkoagulation, Kryogulation) ein schnelles Ansprechen und weiteren Funktionserhalt (Gesichtsfeld). Die Ausreifung neovaskulärer Gefäße (Perizyten) und die sekundäre Formation von Membranen limitiert den Zeitpunkt, zu dem eine medikamentöse Behandlung indiziert ist.

Abstract

Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. Through regulation of haemodynamics, haematopoesis and the immune system, endocrinology and reparative processes, inhibition of VEGF can cause multiple adverse events. Previous data suggest that – even after intravitreal injection – systemic exposure might occur, thus bearing the risk of manifestation of side effects. Experience with intravenous administration of the antibody bevacizumab (Avastin®) pointed to the potential consequences of a pan-VEGF blockade. The change of haemodynamic parameters implies a potential influence on the patient’s morbidity. Studies already conducted during the approval process do not provide sufficient statistical power when evaluating whether systemic events significantly differ between the treatment and control groups. Retinal perfusion showed an altered vascular tone (change in vessel diameter) following anti-VEGF treatment. Physiological fenestration of the choroicapillaris is significantly reduced. Possible effects on the local oxygen supply in ischaemic tissue have to be considered. In contrast to destructive treatment modalities (laser, cryo), VEGF inhibitors promise the prompt and efficient response of retinal neovascularisation and the preservation of a better function (visual fields). The maturation of growing vessels (pericytes) and the secondary formation of membranes are limiting factors with regard to the time-point at which anti-VEGF therapy is most effective. A diligent use of the available drugs has to take into account which types of exudative retinopathy are showing no or only very limited response to the treatment.

Schlüsselwörter

Retina - VEGF - Thrombembolie - Schlaganfall - Bevacizumab (Avastin) - Nebenwirkungen

Key words

retina - VEGF - thromboembolism - stroke - bevacizumab (Avastin) - side effects

Full Text

References

Literatur

1 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285 1182-1186
2 Senger D R, Galli S J, Dvorak A M. et al . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219 983-985
3 Adamis A P, Shima D T, Tolentino M J. et al . Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996; 114 66-71
4 Ferrara N, Gerber H P, Lecouter J. The biology of VEGF and its receptors. Nat Med. 2003; 9 669-676
5 Geitzenauer W, Michels S, Prager F. et al . Early effects of systemic and intravitreal bevacizumab (avastin) therapy for neovascular age-related macular degeneration. Klin Monatsbl Augenheilkd. 2006; 223 822-827
6 Roskoski R Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 2007; 62 179-213
7 Liu L, Simon M C. Regulation of transcription and translation by hypoxia. Cancer Biol Ther. 2004; 3 492-497
8 Liu K, Yang Y, Mansbridge J. Comparison of the stress response to cryopreservation in monolayer and three-dimensional human fibroblast cultures: stress proteins, MAP kinases, and growth factor gene expression. Tissue Eng. 2000; 6 539-554
9 Kucab J E, Dunn S E. Role of IGF-1R in mediating breast cancer invasion and metastasis. Breast Dis. 2003; 17 41-47
10 Cohen T, Nahari D, Cerem L W. et al . Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996; 271 736-741
11 Stocks J, Bradbury D, Corbett L. et al . Cytokines upregulate vascular endothelial growth factor secretion by human airway smooth muscle cells: Role of endogenous prostanoids. FEBS Lett. 2005; 579 2551-2556
12 Finkenzeller G, Marme D, Weich H A. et al . Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res. 1992; 52 4821-4823
13 Ryuto M, Ono M, Izumi H. et al . Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem. 1996; 271 28 220-28 228
14 Pertovaara L, Kaipainen A, Mustonen T. et al . Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem. 1994; 269 6271-6274
15 Carnesecchi S, Carpentier J L, Foti M. et al . Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3. Exp Cell Res. 2006; 312 3413-3424
16 Hyder S M, Murthy L, Stancel G M. Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res. 1998; 58 392-395
17 Haggstrom S, Lissbrant I F, Bergh A. et al . Testosterone induces vascular endothelial growth factor synthesis in the ventral prostate in castrated rats. J Urol. 1999; 161 1620-1625
18 Wang J, Luo F, Lu J J. et al . VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors. Int J Cancer. 2002; 97 163-167
19 Shi B M, Wang X Y, Mu Q L. et al . Expressions of vascular endothelial growth factor in cirrhotic tissues and their relations to proto-oncogene c-fos, c-myc. Hepatobiliary Pancreat Dis Int. 2002; 1 388-391
20 Rak J, Mitsuhashi Y, Bayko L. et al . Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995; 55 4575-45 780
21 Ravi R, Mookerjee B, Bhujwalla Z M. et al . Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000; 14 34-44
22 Bautz F, Rafii S, Kanz L. et al . Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment. Exp Hematol. 2000; 28 700-706
23 Tolosa L, Mir M, Asensio V J. et al . Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem. 2008; 105 1080-1090
24 Boer K, Troost D, Spliet W G. et al . Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB. Acta Neuropathol. 2008; E-Pub
25 Nakamura K, Zen Y, Sato Y. et al . Vascular endothelial growth factor, its receptor Flk-1, and hypoxia inducible factor-1alpha are involved in malignant transformation in dysplastic nodules of the liver. Hum Pathol. 2007; 38 1532-1546
26 Compernolle V, Brusselmans K, Acker T. et al . Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med. 2002; 8 702-710
27 Barleon B, Sozzani S, Zhou D. et al . Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996; 87 3336-3343
28 Clauss M, Weich H, Breier G. et al . The vascular endothelial growth factor receptor Flt-1 mediates biological activitiesüüImplications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem. 1996; 271 17 629-17 634
29 Duyndam M C, Hilhorst M C, Schluper H M. et al . Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts. Am J Pathol. 2002; 160 537-548
30 Norrby K. Mast cells and angiogenesis. APMIS. 2002; 110 355-371
31 Feistritzer C, Kaneider N C, Sturn D H. et al . Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. Am J Respir Cell Mol Biol. 2004; 30 729-735
32 Paulis de A, Prevete N, Fiorentino I. et al . Expression and functions of the vascular endothelial growth factors and their receptors in human basophils. J Immunol. 2006; 177 7322-7331
33 Casella I, Feccia T, Chelucci C. et al . Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood. 2003; 101 1316-1323
34 Gerber H P, Malik A K, Solar G P. et al . VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002; 417 954-958
35 Tombran-Tink J, Barnstable C J. Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone. Biochem Biophys Res Commun. 2004; 316 573-579
36 Shui Y B, Wang X, Hu J S. et al . Vascular endothelial growth factor expression and signaling in the lens. Invest Ophthalmol Vis Sci. 2003; 44 3911-9
37 Yoeruek E, Spitzer M S, Tatar O. et al . Safety profile of bevacizumab on cultured human corneal cells. Cornea. 2007; 26 977-982
38 Yang X, Cepko C L. Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci. 1996; 16 6089-6099
39 Ablonczy Z, Crosson C E. VEGF modulation of retinal pigment epithelium resistance. Exp Eye Res. 2007; 85 762-771
40 Saint-Geniez M, Maldonado A E, D’Amore P A. VEGF expression and receptor activation in the choroid during development and in the adult. Invest Ophthalmol Vis Sci. 2006; 47 3135-3142
41 Smith C P, Steinle J J. Changes in growth factor expression in normal aging of the rat retina. Exp Eye Res. 2007; 85 817-824
42 Boyd S R, Tan D, Bunce C. et al . Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window. Br J Ophthalmol. 2002; 86 448-452
43 Gille J. Antiangiogenic cancer therapies get their act together: current developments and future prospects of growth factor- and growth factor receptor-targeted approaches. Exp Dermatol. 2006; 15 175-186
44 Bates D O. The chronic effect of vascular endothelial growth factor on individually perfused frog mesenteric microvessels. J Physiol. 1998; 513 (Pt 1) 225-233
45 Nagy J A, Benjamin L, Zeng H. et al . Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008; E-Pub
46 Grove C S, Lee Y C. Vascular endothelial growth factor: the key mediator in pleural effusion formation. Curr Opin Pulm Med. 2002; 8 294-301
47 Völcker M, Peters S, Inhoffen W. et al . Early antiexudative response – OCT monitoring after intravitreal bevacizumab injection]. Ophthalmologe. 2006; 103 476-483
48 Spitzer M S, Ziemssen F, Yoeruek E. et al . Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg. 2008; 34 70-75
49 Ziemssen F, Deuter C M, Stuebiger N. et al . Weak transient response of chronic uveitic macular edema to intravitreal bevacizumab (Avastin). Graefes Arch Clin Exp Ophthalmol. 2007; 245 917-918
50 Angelo L S, Kurzrock R. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007; 13 2825-2830
51 Clauss M, Gerlach M, Gerlach H. et al . Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990; 172 1535-1545
52 Min J K, Lee Y M, Kim J H. et al . Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. Circ Res. 2005; 96 300-307
53 Yoo S A, Bae D G, Ryoo J W. et al . Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-alpha and IL-6 by human monocytes. J Immunol. 2005; 174 5846-5855
54 Hattori K, Dias S, Heissig B. et al . Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001; 193 1005-1014
55 Reinders M E, Sho M, Izawa A. et al . Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest. 2003; 112 1655-1665
56 Mor F, Quintana F J, Cohen I R. Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol. 2004; 172 4618-4623
57 Proescholdt M A, Jacobson S, Tresser N. et al . Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J Neuropathol Exp Neurol. 2002; 61 914-925
58 Watanabe H, Mamelak A J, Wang B. et al . Anti-vascular endothelial growth factor receptor-2 (Flk-1 /KDR) antibody suppresses contact hypersensitivity. Exp Dermatol. 2004; 13 671-681
59 Halin C, Tobler N E, Vigl B. et al . VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood. 2007; 110 3158-3167
60 Bock F, Onderka J, Dietrich T. et al . Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci. 2007; 48 2545-2552
61 Ziemssen F, Warga M, Neuhann I M. et al . Does intravitreal injection of bevacizumab have an effect on the blood-aqueus barrier function?. Br J Ophthalmol. 2006; 90 922
62 Pepper M S. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol. 2001; 21 1104-1117
63 Behzadian M A, Windsor L J, Ghaly N. et al . VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. FASEB J. 2003; 17 752-754
64 Lee K S, Park S J, Kim S R. et al . Inhibition of VEGF blocks TGF-{beta}1 production through a PI 3K/Akt signalling pathway. Eur Respir J. 2008; 31 523-531
65 Wynn T A. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008; 214 199-210
66 Friedlander M. Fibrosis and diseases of the eye. J Clin Invest. 2007; 117 576-586
67 Jonas J B, Spandau U H, Schlichtenbrede F. Intravitreal bevacizumab for filtering surgery. Ophthalmic Res. 2007; 39 121-122
68 Yoeruek E, Ziemssen F, Henke-Fahle S. et al . Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol Scand. 2007; E-Pub
69 Hsieh M Y, Chen W Y, Jiang M J. et al . Interleukin-20 promotes angiogenesis in a direct and indirect manner. Genes Immun. 2006; 7 234-242
70 Hartlapp I, Abe R, Saeed R W. et al . Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J. 2001; 15 2215-2224
71 Scappaticci F A, Fehrenbacher L, Cartwright T. et al . Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005; 91 173-180
72 Ko J, Ross J, Awad H. et al . The effects of ZD 6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice. J Surg Res. 2005; 129 251-259
73 Street J, Bao M, deGuzman L. et al . Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002; 99 9656-9661
74 Mac G F, Ji J W, Popel A S. VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle. J Appl Physiol. 2007; 102 722-734
75 Wei W, Chen Z W, Yang Q. et al . Vasorelaxation induced by vascular endothelial growth factor in the human internal mammary artery and radial artery. Vascul Pharmacol. 2007; 46 253-259
76 Yang R, Thomas G R, Bunting S. et al . Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol. 1996; 27 838-844
77 Lin M I, Sessa W C. Vascular endothelial growth factor signaling to endothelial nitric oxide synthase: more than a FLeeTing moment. Circ Res. 2006; 99 666-668
78 Genentech Inc .Avastin™ (bevacizumab) for intravenous use [Package insert]. South San Francisco CA; 2004
79 Kabbinavar F, Hurwitz H I, Fehrenbacher L. et al . Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21 60-65
80 Zhu X, Shenhong W, Dahut W L. et al . Risks of Proteinuria and Hypertension with Bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007; 49 186-193
81 Zachary I. Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals. 2005; 14 207-221
82 Kilic U, Kilic E, Jarve A. et al . Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1 / 2 and Akt pathways. J Neurosci. 2006; 26 12 439-12 446
83 Schiera G, Proia P, Alberti C. et al . Neurons produce FGF2 and VEGF and secrete them at least in part by shedding extracellular vesicles. J Cell Mol Med. 2007; 11 1384-1394
84 Schanzer A, Wachs F P, Wilhelm D. et al . Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol. 2004; 14 237-248
85 Famiglietti E V, Stopa E G, McGookin E D. et al . Immunocytochemical localization of vascular endothelial growth factor in neurons and glial cells of human retina. Brain Res. 2003; 969 195-204
86 Nishijima K, Ng Y S, Zhong L. et al . Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol. 2007; 171 53-67
87 Eremina V, Cui S, Gerber H. et al . Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol. 2006; 17 724-735
88 Kasahara Y, Tuder R M, Taraseviciene-Stewart L. et al . Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest. 2000; 106 1311-1319
89 Tuder R M, Zhen L, Cho C Y. et al . Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol. 2003; 29 88-97
90 Advani A, Kelly D J, Advani S L. et al . Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. Proc Natl Acad Sci U S A. 2007; 104 14 448-14 453
91 Ostendorf T, Kunter U, Eitner F. et al . VEGF(165) mediates glomerular endothelial repair. J Clin Invest. 1999; 104 913-923
92 Eremina V, Jefferson J A, Kowalewska J. et al . VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358 1129-136
93 Wang J F, Milosveski V, Schramek C. et al . Presence and possible role of vascular endothelial growth factor in thyroid cell growth and function. J Endocrinol. 1998; 157 5-12
94 Lammert E, Gu G, McLaughlin M. et al . Role of VEGF-A in vascularization of pancreatic islets. Curr Biol. 2003; 13 1070-1074
95 Kamba T, Tam B Y, Hashizume H. et al . VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006; 290 H560-H576
96 Inoue M, Hager J H, Ferrara N. et al . VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell. 2002; 1 193-202
97 Maharaj A S, Walshe T E, Saint-Geniez M. et al . VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med. 2008; 205 491-501
98 Gerber H P, Hillan K J, Ryan A M. et al . VEGF is required for growth and survival in neonatal mice. Development. 1999; 126 1149-1159
99 Hetland M L, Christensen I J, Lottenburger T. et al . Circulating VEGF as a biological marker in patients with rheumatoid arthritis? Preanalytical and biological variability in healthy persons and in patients. Dis Markers. 2008; 24 1-10
100 Iacobellis G, Cipriani R, Gabriele A. et al . High circulating vascular endothelial growth factor (VEGF) is related to a better systolic function in diabetic hypertensive patients. Cytokine. 2004; 27 25-30
101 Csaky K G, Gordiyenko N, Rabena M G. et al . Pharmakokinetics of intravitreal bevacizumab in humans. Invest Ophth Vis Sci. 2007; 48 A4936
102 Heiduschka P, Fietz H, Hofmeister S. et al . Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci. 2007; 48 2814-2823
103 Avery R L, Pearlman J, Pieramici D J. et al . Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006; 113 1695-1615
104 Rodrigues E B, Shiroma H, Meyer C H. et al . Metrorrhagia after intravitreal injection of bevacizumab. Acta Ophthalmol Scand. 2007; 85 915-916
105 Gillies M C, Wong T Y. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2007; 356 748-749
106 Verheul H M, Lolkema M P, Qian D Z. et al . Platelets take up the monoclonal antibody bevacizumab. Clin Cancer Res. 2007; 13 5341-5347
107 Ziemssen F, Zhu Q, Peters S. et al . Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: Preliminary findings of a pilot study. Int Ophthalmol. 2008; E-Pub
108 Ziemssen F, Folprecht G, Ziemssen T. Intravitreous bevacizumab and blood pressure: does ‘safe’ mean ‘safe enough’?. Acta Ophthalmol Scand. 2007; 85 573-574
109 McGimpsey S J, Gillies M C. Treatment of macular degeneration – controversy and hope. Br J Ophthalmol. 2008; 92 436-437
110 Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006; 354 980-982
111 Ziemssen F, Grisanti S, Bartz-Schmidt K U. The international intravitreal bevacizumab safety survey. Br J Ophthalmol. 2006; 90 1440-1441
112 Kim I, Ryan A M, Rohan R. et al . Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci. 1999; 40 2115-2121
113 Blaauwgeers H G, Holtkamp G M, Rutten H. et al . Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol. 1999; 155 421-428
114 Kaempf S, Johnen S, Salz A K. et al . Effects of Bevacizumab (Avastin) on retinal cells in organotypic culture. Invest Ophthalmol Vis Sci. 2008; E-Pub
115 Lüke M, Warga M, Ziemssen F. et al . Effects of bevacizumab on retinal function in isolated vertebrate retina. Br J Ophthalmol. 2006; 90 1178-1182
116 Peters S, Heiduschka P, Julien S. et al . Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol. 2007; 143 995-1002
117 Inai T, Mancuso M, Hashizume H. et al . Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004; 165 35-52
118 Mancuso M R, Davis R, Norberg S M. et al . Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006; 116 2610-2621
119 Geisen P, Peterson L J, Martiniuk D. et al . Neutralizing antibody to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity. Mol Vis. 2008; 14 345-357
120 Soliman W, Vinten M, Sander B. et al . Optical coherence tomography and vessel diameter changes after intravitreal bevacizumab in diabetic macular oedema. Acta Ophthalmol Scand. 2007; E-Pub
121 Baffert F, Le T, Sennino B. et al . Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006; 290 H547-H559
122 Fung A E, Rosenfeld P J, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol. 2006; 90 1344-1349
123 Wu L, Martinez-Castellanos M A, Quiroz-Mercado H. et al . Twelve-month safety of intravitreal injections of bevacizumab (Avastin®): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008; 246 81-87
124 Shima C, Sakaguchi H, Gomi F. et al . Complications in patients after intravitreal injection of bevacizumab. Acta Ophthalmol Scand. 2007; E-Pub
125 Helotera H, Alitalo K. The VEGF family, the inside story. Cell. 2007; 130 591-592
126 Gruchala M, Roy H, Bhardwaj S. et al . Gene therapy for cardiovascular diseases. Curr Pharm Des. 2004; 10 407-423
127 Lambrechts D, Storkebaum E, Morimoto M. et al . VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003; 34 383-394
128 Nicoletti J N, Shah S K, McCloskey D P. et al . Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience. 2008; 151 232-241
129 Karkkainen M J, Saaristo A, Jussila L. et al . A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A. 2001; 98 12 677-12 682
130 Maynard S E, Min J Y, Merchan J. et al . Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111 649-658
131 Celletti F L, Waugh J M, Amabile P G. et al . Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001; 7 425-429
132 Detmar M, Brown L F, Claffey K P. et al . Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. 1994; 180 1141-1146
133 Yano K, Liaw P C, Mullington J M. et al . Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med. 2006; 203 1447-1458

Dr. Focke Ziemssen

Eberhard-Karl-Universität Tübingen, Department für Augenheilkunde

Schleichstr. 12

72076 Tübingen

Phone: ++ 49/70 71/2 98 47 61

Fax: ++ 49/70 71/29 52 15

Email: Focke.Ziemssen@med.uni-tuebingen.de