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Glycomed, Inc., Alameda, California 94501 [R. E. G.]; Watsonia North 3087 Victoria, Australia [D. G.]; Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510 [H. G. F.]; and Department of Diagnostic Radiology, Section of Ultrasound, Yale University School of Medicine, New Haven, Connecticut 06510 [L. A. F.]
The inhibitor N-[2R-2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-L-tryptophan methylamide specifically blocks several matrix metalloproteases, enzymes which are thought to be involved in angiogenesis. An extract of Walker 256 carcinoma in Hydron pellets implanted in the corneas of Sprague-Dawley rats was used to stimulate angiogenesis from the vessels of the limbus. Angiogenesis was graded visually as the distance penetrated into the cornea and the number of vessels generated. The vessel area was also measured by image analysis using Image 1 software. Continuous i.v. administration of N-[2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-L-tryptophan methylamide at 32 mg/kg/day (n = 17) via syringe pump reduced vessel number [25.06 ± 5.9 (SEM) compared to 65.33 ± 9.0] and vessel area (26.14 ± 3.2 mm2 compared with 40.96 ± 4.6 mm2), but not distance penetrated, compared to vehicle-treated control eyes after 6 days. These results confirm the suspected role for matrix metalloproteases in angiogenesis and suggest that inhibitors of these enzymes may be angiostatic agents.
1 This work was supported in part by NIH Grant HL27368
2 To whom requests for reprints should be addressed, at Glycomed, Inc., 860 Atlantic Ave., Alameda, CA 94501.
Received 4/18/94. Accepted 6/27/94.
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