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F. A. Lattanzio, Jr., P. Loose-Thurman, K. A. Schellenberg, S. Samudre, A. Hosseini, P. B. Williams; OC-10X, a Non-Toxic Inhibitor of Tubulin, Inhibits Vascular Endothelial Cell Proliferation Both in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2008;49(13):856. doi: https://doi.org/.
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OC-10X is a new drug in development for the treatment of wet age-related macular degeneration (AMD). Wet AMD is associated with the growth of abnormal, fragile blood vessels. This study compared OC-10X’s effect on endothelial cell proliferation with anti-VEGF drugs and examined its pharmacokinetic and toxic effects after topical and intravitreal (IVT) administration.
To test vascular cell growth inhibition, 10nM-100µM OC-10X, pan tubulin inhibitor ,combretastatin, and the anti-VEGFs, bevacizumab or ranibizumab, were applied to bovine and human retinal endothelial cells during the log growth phase over 5 days, +/- 10nM VEGF. Toxicological and pharmacokinetic studies were also performed on SD rats and Dutch belted rabbits using unlabeled OC-10X and 14C-OC-10X and by tonometry, slit lamp, confocal microscopy and multifocal electroretinogram (ERG).
In vitro, 3 µM OC-10X half maximally inhibited bovine cell growth, both +/-VEGF, as did combretastatin. Neither ranibizumab (to 1000 µg/ml) or bevacizumab (to 2500 µg/ml) inhibited bovine cell growth. In the human cell model, 3 µM OC-10X half maximally inhibited as did combretastatin, but bevacizumab or ranibizumab inhibited growth in the presence of VEGF. In vivo, intravenous, IVT and topical OC-10X demonstrated no ocular or gross systemic toxicity in the rat. In the rat and rabbit, topical application of single doses reached the retina. In chronic (14 d) rat studies, topical administration of 14C-OC-10X cleared through kidneys into urine, with some elimination occurring in the feces. Topical 14C-OC-10X penetrated the cornea/sclera to reach the retina, with subclinical levels in the brain, plasma and other organs. Multifocal ERG showed no retinal toxicity as there were no functional deficits.
In cell models, OC-10x reduces cell proliferation in the presence or absence of VEGF, as does combretastatin. However, unlike combretastatin, there is no OC-10X organ toxicity in vivo at therapeutic doses in both rat and rabbit models. In addition, topically applied OC-10X enters the retina and achieves concentrations that would inhibit endothelial cell proliferation based on cell culture models. Both topical and IVT OC-10X have the potential to reduce CNV with little toxicity in vivo.
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