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Timothy William Corson, Christian Briggs, Rania S. Sulaiman, Asmaa Mahoui, Kamakshi Sishtla, Mehdi Shadmand; A non-cytotoxic compound blocks angiogenesis and decreases tumor burden in the TAg-RB retinoblastoma mouse. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1774.
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Cytotoxic systemic or local chemotherapy is a mainstay of retinoblastoma therapy but is associated with significant side effects. Antiangiogenic therapy could avoid some of this toxicity. We developed the novel antiangiogenic compound SH-11037, which likely acts as a soluble epoxide hydrolase inhibitor. SH-11037 blocks angiogenesis in vitro and in murine ocular neovascularization models, making it a candidate for antiangiogenic retinoblastoma therapy. Here, we explored the effects of SH-11037 on retinoblastoma cells in culture and as a treatment for retinoblastoma in the TAg-RB transgenic mouse model.
We assessed the effects of SH-11037 on proliferation of Y79 retinoblastoma cells and ARPE-19 “normal” retinal pigment epithelial cells by alamarBlue proliferation assays. For therapeutic evaluation, TAg-RB mice were intravitreally injected with SH-11037 or vehicle to a final vitreous concentration of 10 µM weekly starting at 7 or 8 weeks of age with sacrifice and enucleation at 10 or 11 weeks. We followed tumor progression by optical coherence tomography in vivo and histopathological analysis post-mortem. Percent tumor burden in each eye was compared between cohorts and treatments by two-way ANOVA.
SH-11037 did not block the growth of retinoblastoma or retinal pigment epithelial cells in culture, suggestive of a lack of toxicity. However, in transgenic mice with retinoblastoma, SH-11037 significantly reduced tumor burden over vehicle (up to 26% reduction, p=0.022). No adverse effects were observed with weekly compound injections.
SH-11037 is not toxic to tumor or healthy cells of the eye, but when administered by intravitreal injection may be a candidate for retinoblastoma treatment by blocking angiogenesis. Further validation of the possibility of intravitreal, antiangiogenic retinoblastoma therapy using other drugs and other preclinical models is indicated.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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