Abstract
Purpose: :
To test a novel isoquinoline derivative, EDL-155, in cultured retinoblastoma and in an animal model of retinoblastoma.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: retinoblastoma • apoptosis/cell death • drug toxicity/drug effects