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Graefe's Archive for Clinical and Experimental Ophthalmology
Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology 6/2005

01.06.2005 | Laboratory Investigation

Intravitreal injection of specific receptor tyrosine kinase inhibitor PTK787/ZK222 584 improves ischemia-induced retinopathy in mice

verfasst von: Philip Maier, Anke S. Unsoeld, Bernd Junker, Gottfried Martin, Joachim Drevs, Lutz L. Hansen, Hansjürgen T. Agostini

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 6/2005

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Abstract

Background

Retinal neovascularisation occurs under the influence of angiogenic factors that are induced by hypoxia, like vascular endothelial growth factor (VEGF), which is one of the major mediators. PTK/ZK inhibits VEGF signal transduction by blocking the tyrosine kinase of all three VEGF receptors. PTK/ZK is currently being evaluated in clinical trials for angioinhibitory therapy in tumour patients. To avoid potential systemic side effects, local application would be desirable for the treatment of ischemic retinopathies in humans. We therefore investigated the effect of intravitreally applied PTK/ZK in a mouse model for ischemia-induced retinopathy.

Methods

C57BL/6J mice were placed in 75% oxygen on postnatal day 7. On day 12, they were treated with an intravitreal injection of PTK/ZK (5 μM or 40 μM) in one eye and buffer solution in the fellow eye. Afterwards, the animals were kept in room air until intracardial perfusion with fluorescein-dextran on day 17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated using a standardised retinopathy score.

Results

A single intravitreal injection of 40 μM PTK/ZK reduced angioproliferative changes compared to the control eye of each animal (n=37). The difference in retinopathy scores was highly significant (P=0.002, Wilcoxon signed-rank test). Injection of 5 μM PTK/ZK did not show a significant antiangiogenic effect.

Conclusions

Tyrosine kinase inhibitors are promising substances not only in cancer therapy, but also in the treatment of ischemic retinopathies that are mediated by VEGF. We showed that in a mouse model for ischemia-induced retinopathy a single intravitreal injection of 40 μM PTK/ZK is capable of significantly reducing angioproliferative retinopathy. The local application of PTK/ZK could be a new way to treat ischemic ocular diseases such as diabetic retinopathy in humans.
Literatur
1.
Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450
2.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders [see comments]. N Engl J Med 331:1480–1487 (see comments in 331(22):1519–1520)CrossRefPubMed
3.
Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92:10457–10461
4.
Boden KT, Fiedler U, Marmé D, Hansen LL, Agostini HT (2001) Therapy of angioproliferative retinopathy with soluble VEGF- and Tie- 2- receptors in a mouse model. Ophthalmologe 98:23
5.
Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Bruggen J, Buchdunger E, Cozens R, Ferrari S, Furet P, Hofmann F, Martiny-Baron G, Mestan J, Rosel J, Sills M, Stover D, Acemoglu F, Boss E, Emmenegger R, Lasser L, Masso E, Roth R, Schlachter C, Vetterli W (2000) New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 43:2310–2323CrossRefPubMed
6.
Clauss M (2000) Molecular biology of the VEGF and the VEGF receptor family. Semin Thromb Hemost 26:561–569 (Review, 106 refs)CrossRefPubMed
7.
D’Amato R, Wesolowski E, Smith LE (1993) Microscopic visualization of the retina by angiography with high-molecular-weight fluorescein-labeled dextrans in the mouse. Microvasc Res 46:135–142CrossRefPubMed
8.
Drevs J, Hofmann I, Hugenschmidt H, Wittig C, Madjar H, Muller M, Wood J, Martiny-Baron G, Unger C, Marme D (2000) Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60:4819–4824PubMed
9.
Drevs J, Mross K, Fuxius S, Müller M, Putz B, Laurent D, Dugan M, Peng B, Chong J, Henry A, Marme D, Unger C (2001) A phase I dose-escalating and pharmacokinetic (PK) study of the VEGF-receptor-inhibitor PTK787/ZK222548 (PTK/ZK) in patients with liver metastases of advanced cancer. Proc ASCO 20:a398
10.
Drevs J, Muller-Driver R, Wittig C, Fuxius S, Esser N, Hugenschmidt H, Konerding MA, Allegrini PR, Wood J, Hennig J, Unger C, Marme D (2002) PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res 62:4015–4022PubMed
11.
Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949CrossRefPubMed
12.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMed
13.
Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL, Albertsson-Wikland K, Carlsson B, Niklasson A, Sjodell L, LeRoith D, Senger DR, Smith LE (2001) Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA 98:5804–5808
14.
Higgins RD, Yu K, Sanders RJ, Nandgaonkar BN, Rotschild T, Rifkin DB (1999) Diltiazem reduces retinal neovascularization in a mouse model of oxygen induced retinopathy. Curr Eye Res 18:20–27CrossRefPubMed
15.
Kahn HA, Hiller R (1974) Blindness caused by diabetic retinopathy. Am J Ophthalmol 78:58–67
16.
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844CrossRef
17.
Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122:3829–3837PubMed
18.
Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333–13340
19.
Lin B, Podar K, Gupta D, Tai YT, Li S, Weller E, Hideshima T, Lentzsch S, Davies F, Li C, Weisberg E, Schlossman RL, Richardson PG, Griffin JD, Wood J, Munshi NC, Anderson KC (2002) The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res 62:5019–5026PubMed
20.
Malecaze F, Clamens S, Simorre-Pinatel V, Mathis A, Chollet P, Favard C, Bayard F, Plouet J (1994) Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol 112:1476–1482
21.
McLeod DS, Taomoto M, Cao J, Zhu Z, Witte L, Lutty GA (2002) Localization of VEGF receptor-2 (KDR/Flk-1) and effects of blocking it in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43:474–482
22.
McMahon G (2000) VEGF receptor signaling in tumor angiogenesis. Oncologist 5:3–10PubMed
23.
Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846CrossRefPubMed
24.
Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization [see comments]. Am J Pathol 151:281–291 (see comments in 151(1):13–23, 152(5):1397–1398)PubMed
25.
Ozaki H, Hayashi H, Vinores SA, Moromizato Y, Campochiaro PA, Oshima K (1997) Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 64:505–517CrossRefPubMed
26.
Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM, Campochiaro PA (2000) Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol 156:697–707PubMed
27.
Pe’er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E (1995) Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases [see comments]. Lab Invest 72:638–645 (see comments in 72(6):615–618)PubMed
28.
Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909
29.
Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848CrossRefPubMed
30.
Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE (1996) Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 93:4851–4856
31.
Seo MS, Kwak N, Ozaki H, Yamada H, Okamoto N, Yamada E, Fabbro D, Hofmann F, Wood JM, Campochiaro PA (1999) Dramatic inhibition of retinal and choroidal neovascularization by oral administration of a kinase inhibitor. Am J Pathol 154:1743–1753PubMed
32.
Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1:182–193PubMed
33.
Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845CrossRefPubMed
34.
Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111
35.
Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR (1999) Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 5:1390–1395CrossRefPubMed
36.
Solorzano CC, Baker CH, Bruns CJ, Killion JJ, Ellis LM, Wood J, Fidler IJ (2001) Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biother Radiopharm 16:359–370
37.
Sone H, Kawakami Y, Segawa T, Okuda Y, Sekine Y, Honmura S, Suzuki H, Yamashita K, Yamada N (1999) Effects of intraocular or systemic administration of neutralizing antibody against vascular endothelial growth factor on the murine experimental model of retinopathy. Life Sci 65:2573–2580CrossRefPubMed
38.
Thomas AL, Morgan B, Drevs J, Unger C, Wiedenmann B, Vanhoefer U, Laurent D, Dugan M, Steward WP (2003) Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin Oncol 30:32–38
39.
Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O’Reilly T, Persohn E, Rosel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60:2178–2189PubMed
Metadaten
Titel
Intravitreal injection of specific receptor tyrosine kinase inhibitor PTK787/ZK222 584 improves ischemia-induced retinopathy in mice
verfasst von
Philip Maier
Anke S. Unsoeld
Bernd Junker
Gottfried Martin
Joachim Drevs
Lutz L. Hansen
Hansjürgen T. Agostini
Publikationsdatum
01.06.2005
Erschienen in
Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 6/2005
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-004-1021-9

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