Synthetic and natural MMP inhibitors substantially reduce growth factor–stimulated angiogenesis.

Collagen was copolymerized with buffer alone, bFGF/VEGF, or bFGF/VEGF plus indicated metalloproteinase inhibitors, prior to placement of the collagen implant on the chick CAM. The embryos containing the implants were incubated for 66 hours, with topical addition of inhibitors at 12, 24, 36, and 48 hours. At the end of the incubation, the new vessels appearing in the collagen implants were scored as described in “Materials and methods.” (A) MMP inhibitor BB3103 was added at an initial dose of 1.4 μg/implant with 4 subsequent topical doses of 0.24 μg each. Data represent 2 pooled experiments: control, n = 15 implants; bFGF/VEGF, n = 16; and bFGF/VEGF/BB3103, n = 16. Results of statistical analysis performed using Wilcoxon-signed rank test on matched pairs are as follows: bFGF/VEGF versus buffer control,P = .001; bFGF/VEGF versus bFGF/VEGF/BB3103,P < .01, and buffer control versus bFGF/VEGF/BB3103,P > .05. (B) NTIMP-1 was added at an initial dose of 1.8 μg/implant with 4 subsequent topical doses of 1.8 μg each. Data represent 4 pooled experiments: control, n = 25 implants; bFGF/VEGF, n = 27; and bFGF/VEGF/NTIMP-1, n = 27. Results of statistical analysis are as follows: bFGF/VEGF versus buffer control,P < .001; bFGF/VEGF versus bFGF/VEGF/NTIMP-1,P < .001; buffer control versus bFGF/VEGF/NTIMP-1,P < .05.