help button home button Am J Pathol Angiogenesis Meeting
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seo, M. S.
Right arrow Articles by Campochiaro, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seo, M. S.
Right arrow Articles by Campochiaro, P. A.
(American Journal of Pathology. 1999;154:1743-1753.)
© 1999 American Society for Investigative Pathology

Regular Articles

Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

Man Seong Seo*, Nohoon Kwak*, Hiroaki Ozaki*, Haruhiko Yamada*, Naoyuki Okamoto*, Eri Yamada*, Doriano Fabbro{dagger}, Francesco Hofmann{dagger}, Jeanette M. Wood{dagger} and Peter A. Campochiaro*

From the Departments of Ophthalmology and Neuroscience,*
The Johns Hopkins University School of Medicine, Baltimore, Maryland, and the Division of Oncology Research,{dagger}
Pharmaceutical Division, Research and Development, Novartis Ltd. Pharmaceuticals, Inc., Basel, Switzerland

The most common cause of new blindness in young patients is retinal neovascularization, and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment, but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study, we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family, along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization.




This article has been cited by other articles:


Home page
 J Clin PharmacolHome page
Y. Wang, O. Q. P. Yin, P. Graf, J. C. Kisicki, and H. Schran
Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus
J. Clin. Pharmacol., June 1, 2008; 48(6): 763 - 775.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
R. Lima e Silva, J. Shen, S. F. Hackett, S. Kachi, H. Akiyama, K. Kiuchi, K. Yokoi, M. C. Hatara, T. Lauer, S. Aslam, et al.
The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization
FASEB J, October 1, 2007; 21(12): 3219 - 3230.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. Campos, J. Amaral, S. P. Becerra, and R. N. Fariss
A Novel Imaging Technique for Experimental Choroidal Neovascularization
Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5163 - 5170.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
H. Akiyama, K. A. Mohamedali, R. L. e Silva, S. Kachi, J. Shen, C. Hatara, N. Umeda, S. F. Hackett, S. Aslam, M. Krause, et al.
Vascular Targeting of Ocular Neovascularization with a Vascular Endothelial Growth Factor121/Gelonin Chimeric Protein
Mol. Pharmacol., December 1, 2005; 68(6): 1543 - 1550.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
K. Anzai, S. Yoneya, P. L. Gehlbach, D. Imai, L. L. Wei, and K. Mori
Laser Photocoagulation and, to a Lesser Extent, Photodynamic Therapy Target and Enhance Adenovirus Vector-Mediated Gene Transfer in the Rat Retina
Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3883 - 3891.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. L. e Silva, Y. Saishin, Y. Saishin, H. Akiyama, S. Kachi, S. Aslam, B. Rogers, T. Deering, Y. Y. Gong, S. F. Hackett, et al.
Suppression and Regression of Choroidal Neovascularization by Polyamine Analogues
Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3323 - 3330.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
A. Brafman, I. Mett, M. Shafir, H. Gottlieb, G. Damari, S. Gozlan-Kelner, V. Vishnevskia-Dai, R. Skaliter, P. Einat, A. Faerman, et al.
Inhibition of Oxygen-Induced Retinopathy in RTP801-Deficient Mice
Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3796 - 3805.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
D. S. Fong, L. P. Aiello, F. L. Ferris III, and R. Klein
Diabetic Retinopathy
Diabetes Care, October 1, 2004; 27(10): 2540 - 2553.
[Full Text] [PDF]

Home page
 Arch OphthalmolHome page
M. A. Zarbin
Current Concepts in the Pathogenesis of Age-Related Macular Degeneration
Arch Ophthalmol, April 1, 2004; 122(4): 598 - 614.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
P. A. Campochiaro
Reduction of Diabetic Macular Edema by Oral Administration of the Kinase Inhibitor PKC412
Invest. Ophthalmol. Vis. Sci., March 1, 2004; 45(3): 922 - 931.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Q. D. Nguyen, S. M. Shah, E. Van Anden, J. U. Sung, S. Vitale, and P. A. Campochiaro
Supplemental Oxygen Improves Diabetic Macular Edema: A Pilot Study
Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 617 - 624.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Y. Saishin, R. L. Silva, Y. Saishin, K. Callahan, C. Schoch, M. Ahlheim, H. Lai, F. Kane, R. K. Brazzell, D. Bodmer, et al.
Periocular Injection of Microspheres Containing PKC412 Inhibits Choroidal Neovascularization in a Porcine Model
Invest. Ophthalmol. Vis. Sci., November 1, 2003; 44(11): 4989 - 4993.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
T. A. Ciulla, A. G. Amador, and B. Zinman
Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies
Diabetes Care, September 1, 2003; 26(9): 2653 - 2664.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
H. Nambu, R. Nambu, M. Melia, and P. A. Campochiaro
Combretastatin A-4 Phosphate Suppresses Development and Induces Regression of Choroidal Neovascularization
Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3650 - 3655.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Y. Saishin, Y. Saishin, K. Takahashi, M.-S. Seo, M. Melia, and P. A. Campochiaro
The Kinase Inhibitor PKC412 Suppresses Epiretinal Membrane Formation and Retinal Detachment in Mice with Proliferative Retinopathies
Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3656 - 3662.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
P. G. McGuire, T. R. Jones, N. Talarico, E. Warren, and A. Das
The Urokinase/Urokinase Receptor System in Retinal Neovascularization: Inhibition by A6 Suggests a New Therapeutic Target
Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2736 - 2742.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
F. Wang, K. G. Rendahl, W. C. Manning, D. Quiroz, M. Coyne, and S. S. Miller
AAV-Mediated Expression of Vascular Endothelial Growth Factor Induces Choroidal Neovascularization in Rat
Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 781 - 790.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
K. Takahashi, Y. Saishin, Y. Saishin, K. Mori, A. Ando, S. Yamamoto, Y. Oshima, H. Nambu, M. B. Melia, D. P. Bingaman, et al.
Topical Nepafenac Inhibits Ocular Neovascularization
Invest. Ophthalmol. Vis. Sci., January 1, 2003; 44(1): 409 - 415.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pathol.Home page
E S Bamberger and C W Perrett
Angiogenesis in epithelian ovarian cancer
Mol. Pathol., December 1, 2002; 55(6): 348 - 359.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Ando, A. Yang, H. Nambu, and P. A. Campochiaro
Blockade of Nitric-Oxide Synthase Reduces Choroidal Neovascularization
Mol. Pharmacol., September 1, 2002; 62(3): 539 - 544.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
K. Mori, P. Gehlbach, A. Ando, D. McVey, L. Wei, and P. A. Campochiaro
Regression of Ocular Neovascularization in Response to Increased Expression of Pigment Epithelium-Derived Factor
Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2428 - 2434.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
K. Mori, P. Gehlbach, S. Yamamoto, E. Duh, D. J. Zack, Q. Li, K. I. Berns, B. J. Raisler, W. W. Hauswirth, and P. A. Campochiaro
AAV-Mediated Gene Transfer of Pigment Epithelium-Derived Factor Inhibits Choroidal Neovascularization
Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1994 - 2000.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
K. Mori, P. Gehlbach, A. Ando, G. Dyer, E. Lipinsky, A. G. Chaudhry, S. F. Hackett, and P. A. Campochiaro
Retina-Specific Expression of PDGF-B Versus PDGF-A: Vascular Versus Nonvascular Proliferative Retinopathy
Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 2001 - 2006.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
E. J. Duh, H. S. Yang, I. Suzuma, M. Miyagi, E. Youngman, K. Mori, M. Katai, L. Yan, K. Suzuma, K. West, et al.
Pigment Epithelium-Derived Factor Suppresses Ischemia-Induced Retinal Neovascularization and VEGF-Induced Migration and Growth
Invest. Ophthalmol. Vis. Sci., March 1, 2002; 43(3): 821 - 829.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
J. Griggs, J. N. Skepper, G. A. Smith, K. M. Brindle, J. C. Metcalfe, and R. Hesketh
Inhibition of Proliferative Retinopathy by the Anti-Vascular Agent Combretastatin-A4
Am. J. Pathol., March 1, 2002; 160(3): 1097 - 1103.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. S. McLeod, M. Taomoto, J. Cao, Z. Zhu, L. Witte, and G. A. Lutty
Localization of VEGF Receptor-2 (KDR/Flk-1) and Effects of Blocking It in Oxygen-Induced Retinopathy
Invest. Ophthalmol. Vis. Sci., February 1, 2002; 43(2): 474 - 482.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Ohno-Matsui, A. Hirose, S. Yamamoto, J. Saikia, N. Okamoto, P. Gehlbach, E. J. Duh, S. Hackett, M. Chang, D. Bok, et al.
Inducible Expression of Vascular Endothelial Growth Factor in Adult Mice Causes Severe Proliferative Retinopathy and Retinal Detachment
Am. J. Pathol., February 1, 2002; 160(2): 711 - 719.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
I. Chowers, E. Banin, Y. Hemo, R. Porat, H. Falk, E. Keshet, J. Pe'er, and A. Panet
Gene transfer by viral vectors into blood vessels in a rat model of retinopathy of prematurity
Br. J. Ophthalmol., August 1, 2001; 85(8): 991 - 995.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Mori, A. Ando, P. Gehlbach, D. Nesbitt, K. Takahashi, D. Goldsteen, M. Penn, C. T. Chen, K. Mori, M. Melia, et al.
Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin
Am. J. Pathol., July 1, 2001; 159(1): 313 - 320.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. J. Propper, A. C. McDonald, A. Man, P. Thavasu, F. Balkwill, J. P. Braybrooke, F. Caponigro, P. Graf, C. Dutreix, R. Blackie, et al.
Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C
J. Clin. Oncol., March 1, 2001; 19(5): 1485 - 1492.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. Lonchampt, L. Pennel, and J. Duhault
Hyperoxia/Normoxia-Driven Retinal Angiogenesis in Mice: A Role for Angiotensin II
Invest. Ophthalmol. Vis. Sci., February 1, 2001; 42(2): 429 - 432.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
V. Stellmach, S. E. Crawford, W. Zhou, and N. Bouck
Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor
PNAS, January 23, 2001; (2001) 31252398.
[Abstract] [Full Text]

Home page
 IOVSHome page
N. Kwak, N. Okamoto, J. M. Wood, and P. A. Campochiaro
VEGF Is Major Stimulator in Model of Choroidal Neovascularization
Invest. Ophthalmol. Vis. Sci., September 1, 2000; 41(10): 3158 - 3164.
[Abstract] [Full Text]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
P. Parsons-Wingerter, K. E. Elliott, J. I. Clark, and A. G. Farr
Fibroblast Growth Factor-2 Selectively Stimulates Angiogenesis of Small Vessels in Arterial Tree
Arterioscler. Thromb. Vasc. Biol., May 1, 2000; 20(5): 1250 - 1256.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
R. S. Kerbel
Tumor angiogenesis: past, present and the near future
Carcinogenesis, March 1, 2000; 21(3): 505 - 515.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
H. Ozaki, M.-S. Seo, K. Ozaki, H. Yamada, E. Yamada, N. Okamoto, F. Hofmann, J. M. Wood, and P. A. Campochiaro
Blockade of Vascular Endothelial Cell Growth Factor Receptor Signaling Is Sufficient to Completely Prevent Retinal Neovascularization
Am. J. Pathol., February 1, 2000; 156(2): 697 - 707.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
V. Stellmach, S. E. Crawford, W. Zhou, and N. Bouck
Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor
PNAS, February 27, 2001; 98(5): 2593 - 2597.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 1999 by the American Society for Investigative Pathology.