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Angiostatin Inhibits and Regresses Corneal Neovascularization
Balamurali K. Ambati, MD;
Antonia M. Joussen, MD;
Jayakrishna Ambati, MD;
Yasufumi Moromizato, MD;
Chandan Guha, MBBS, PhD;
Kashi Javaherian, MD;
Stephen Gillies, PhD;
Michael S. O'Reilly, MD;
Anthony P. Adamis, MD
Arch Ophthalmol. 2002;120:1063-1068.
Objective To determine the ability of angiostatin and the angiostatin-producing
low-metastatic (LM) clone of Lewis lung carcinoma (LLC) to inhibit and regress
corneal neovascularization, as compared with the non–angiostatin-producing
high-metastatic (HM) clone.
Methods Three groups of C57BL6/J mice underwent chemical and mechanical denudation
of corneal and limbal epithelium. One group remained tumor free while the
other 2 were implanted with LLC cells (either the HM or LM clones) subcutaneously
the day before, 2 weeks after, or 4 weeks after denudation. Corneas were harvested
2 weeks after tumor implantation (at 2, 4, and 6 weeks after denudation for
tumor-free mice). Neovascularization was quantified by CD31 immunostaining.
In a second experiment, recombinant angiostatin was delivered continuously
for 2 weeks via an osmotic pump in mice with established corneal neovascularization.
Results The mean percentages of neovascularized corneal area in mice 2 weeks
after LM-LLC implantation were 4.6%, 3.7%, and 37.0%, at 2, 4, and 6 weeks
after scraping, respectively. In contrast, in the mice implanted with HM-LLC,
the corresponding values were 45.4% (P = .01), 90.1%
(P = .03), and 80.3% (P
= .005). For tumor-free mice, the corresponding values were 62.0% (P = .003), 68.9% (P = .03), and 59.3% (P = .06). Mice implanted with angiostatin pumps had a 37.7%
neovascularized corneal area 2 weeks after implantation and 4 weeks after
scraping while mice implanted with sham pumps had 60.5% (P = .007).
Conclusion Angiostatin inhibits and regresses corneal neovascularization induced
by mechanical and alkali corneal injury.
Clinical Relevance This appears to be the first evidence of biologically induced regression
of corneal neovascularization, and the first direct demonstration of angiostatin-induced
regression of neovascularization in any tissue.
From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary,
(Drs B. K. Ambati, Joussen, J. Ambati, Moromizato, and Adamis); Laboratory
for Surgical Research, Children's Hospital (Drs Joussen, Moromizato, Javaherian,
and Adamis), Harvard Medical School, Boston; Department of Radiation Oncology,
Albert Einstein College of Medicine, Bronx, NY (Dr Guha); Lexigen Pharmaceuticals,
Lexington, Mass (Dr Gillies); Division of Radiation Oncology, University of
Texas M. D. Anderson Cancer Center, Houston (Dr O'Reilly).
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