Efficacy of Prinomastat) (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization.
OBJECTIVE
To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization.


METHODS
C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research.


RESULTS
AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg.


CONCLUSIONS
AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.
Shiley Eye Center, University of California, La Jolla, CA 92093-0946, USA.
Claudio
C
Garcia
Dirk-Uwe
DU
Bartsch
Maria E
ME
Rivero
Martin
M
Hagedorn
Charles D
CD
McDermott
Germaine
G
Bergeron-Lynn
Lingyun
L
Cheng
Krzysztof
K
Appelt
William R
WR
Freeman
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D000860:Hypoxia / Q000150:complications; D007274:Injections, Intraperitoneal; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009930:Organic Chemicals; D011247:Pregnancy; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009930:Organic Chemicals; C113282:prinomastat; D008666:Metalloendopeptidases