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Toxicity and intraocular properties of a novel long-acting anti-proliferative and anti-angiogenic compound IMS2186.

Author	Iryna A Falkenstein, Lingyun Cheng, Flossie Wong-Staal, Ajay M Tammewar, Erin C Barron, Gabriel A Silva, Qi-Xiang Li, Dehua Yu, Michelle Hysell, Guohong Liu, Ning Ke, James E Macdonald, William R Freeman
Citation Information	Current eye research, 33:599-609 (2008)
Keywords	Angiogenesis Inhibitors, Animals, Cell Line, Cell Movement, Cell Proliferation, Choroidal Neovascularization, Chromones, Dinoprostone, Disease Models, Animal, Electroretinography, Endothelium, Vascular, Fibroblasts, Fluorescein Angiography, Humans, Mice, NIH 3T3 Cells, Pigment Epithelium of Eye, Rabbits, Rats, Rats, Inbred BN, Tumor Cells, Cultured, Umbilical Veins, Wound Healing
Related Products	ECM512
Pub Med ID	18600493

PURPOSE: To investigate the intraocular properties and toxicity of IMS2186, a small molecule developed as an anti-choroidal neovascularization (anti-CNV) drug. MATERIALS AND METHODS: Cellular toxicity and mechanism of action was tested on cell lines in vitro. Intraocular studies used rabbits for drug dissolution as well as toxicity and rats for the treatment study as well as the toxicity confirmation study. Rabbits' eyes were injected with 2.5 mg of IMS2186 and observed for 36 weeks. Laser-induced CNV in rats was treated with IMS2186, Kenalog, or phosphate-buffered saline (pBS). Fluorescein angiography (FA) and immunohistochemical processing of the globes was performed. RESULTS: The anti-proliferative IC(50) of IMS2186 for human fibroblast cells was 1.0-3.0 microM and 0.3-3.0 microM for human cancer cells; the IC(50) of IMS2186 to inhibit endothelial tube formation was 0.1-0.3 microM. The IC(50) of IMS2186 for inhibiting the production of pro-inflammatory cytokines was 0.3-1 microM. The IC(50) of IMS2186 for inhibiting macrophage migration was 1 micrM. These biological properties were not species specific. IMS2186 can be formulated as a suspension for long-lasting release and when delivered intraocularly, no intraocular toxicity was observed by slit lamp exam, fundus exam, intraocular pressure measurements, or by electroretinography. FA showed a reduction in the leakage in eyes treated with IMS2186 and triamcinolone acetonide; DAPI staining also showed significantly less cellularity in IMS2186-treated lesions as compared to PBS (p = 0.0025). CONCLUSION: IMS2186 may be a safe intraocular therapeutic agent for intraocular proliferation and angiogenesis.