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X. Wang, R. Patil, C. R. Yates, D. D. Miller, E. E. Geisert; A New Isoquinoline Derivative Used to Treat Retinoblastoma in a Rat Model. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1687.
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© ARVO (1962-2015); The Authors (2016-present)
To test a novel isoquinoline derivative, EDL-155, in cultured retinoblastoma and in an animal model of retinoblastoma.
Y79 cells and normal rat astrocytes were treated with serial concentrations of EDL-155 to generate a dose response curve. The effectiveness of this compound was also tested in a rat model in which Luciferase tagged Y79 cells were injected into the vitreous cavity of the eye in newborn rat pups. EDL-155 (20mg/kg daily) was delivered by periocular injections to treat 25 experimental animals and 10 control animals received equivalent dosage of saline.
EDL-155 killed Y79 cells in vitro with an EC50 of 12.5 µM, while the same concentration did not affect normal brain astrocytes. When we examined the EDL-155 treated Y79 cells at the electron microscopic level, there was a lack of viable mitochondria and the presence of autophagosomes wrapped in the characteristic double membranes. We also examined EDL-155 in an animal model of retinoblastoma. EDL-155 may have a high local effectiveness and minimal systemic side effects, for the liver rapidly metabolizes any drug that enters the blood stream. After four doses, delivered over four days, there was a significant decrease (p =0.01) in the size of viable intraocular tumors in the experimental animals relative to the control group. Seven of the 25 rats treated with EDL-155 had no detectable living tumor.
These results indicate that local delivery of EDL-155 may be an effective therapy for treating retinoblastoma with minimal systemic side effects. EDL-155 appears to kill Y79 cells by destroying mitochondria and sending the cells into autophagy induced cell death. It is possible that EDL-155 may act synergistically in combination with other chemotherapeutic agents.
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