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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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