digoxin and Retinoblastoma

To evaluate the ocular safety of intravitreal carboplatin and digoxin injections as a new intravitreal chemotherapy option for retinoblastoma tumor vitreous seeds. Eighteen rabbits were divided randomly into three groups to receive intravitreal injection of Digoxin (6 rabbits), Carboplatin (7 rabbits), or Saline (5 rabbits). In every group, one eye randomly treated with 10 µg Digoxin in 0.1 cc or 1 µg Carboplatin or Saline, and the contralateral eye was considered as the control. All groups underwent three consecutive injections of the drugs with 1-week intervals. Baseline electroretinography (ERG) was recorded from both eyes of all the animals prior to injection and was repeated 1st day, 1st week, and 1st month after the last injection. All rabbits were sacrificed 1 month after the last injection, and histological studies were done. Mean a and b wave amplitudes decreased significantly at 1st day, 1st week, and 1st month after the last intravitreal injection of 10 µg Digoxin in comparison with other groups (p-value: .02). Contradictory, 1 µg Carboplatin injected eyes had minimal ERG changes. There were some nonspecific ERG changes with unclear clinical significance in non-injected contralateral control eyes of Digoxin and Carboplatin groups in comparison with the control eyes of the Saline group. Histological studies revealed considerable neural retinal atrophy in injected eyes of the Digoxin group. Intravitreal 10 µg Digoxin might have more local ocular toxicity in comparison with intravitreal Carboplatin in albino rabbit eyes. Future studies should assess the induced toxicity of intravitreal injection of these drugs on the non-injected contralateral eye.

Topics: Animals; Antineoplastic Agents; Carboplatin; Digoxin; Intravitreal Injections; Rabbits; Retina; Retinoblastoma

To assess in vitro cytotoxic activity and antiangiogenic effect, ocular and systemic disposition, and toxicity of digoxin in rabbits after intravitreal injection as a potential candidate for retinoblastoma treatment.. A panel of two retinoblastoma and three endothelial cell types were exposed to increasing concentrations of digoxin in a conventional (72-hour exposure) and metronomic (daily exposure) treatment scheme. Cytotoxicity was defined as the digoxin concentration that killed 50% of the cells (IC50) and was assessed with a vital dye in all cell types. Induction of apoptosis and cell-cycle status were evaluated by flow cytometry after both treatment schemes. Ocular and systemic disposition after intravitreal injection as well as toxicity was assessed in rabbits. Electroretinograms (ERGs) were recorded before and after digoxin doses and histopathological examinations were performed after enucleation.. Digoxin was cytotoxic to retinoblastoma and endothelial cells under conventional and metronomic treatment. IC50 was comparable between both schedules and induced apoptosis in all cell lines. Calculated vitreous digoxin Cmax was 8.5 μg/mL and the levels remained above the IC50 for at least 24 hours after intravitreal injection. Plasma digoxin concentration was below 0.5 ng/ml. Retinal toxicity was evident after the third intravitreal dose with considerable changes in the ERG and histologic damage to the retina.. Digoxin has antitumor activity for retinoblastoma while exerting antiangiogenic activity in vitro at similar concentrations. Metronomic treatment showed no advantage in terms of dose for cytotoxic effect. Four biweekly injections of digoxin led to local toxicity to the retina but no systemic toxicity in rabbits.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Digoxin; Dose-Response Relationship, Drug; Electroretinography; Enzyme Inhibitors; Flow Cytometry; Follow-Up Studies; Humans; Intravitreal Injections; Neoplasms, Experimental; Rabbits; Retina; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Preclinical studies demonstrate that cardiac glycosides such as ouabain and digoxin have antitumor effects on retinoblastoma cells in vitro and in a xenograft murine model of retinoblastoma.. Based on these findings, we report a case of intra-arterial followed by systemic oral digoxin therapy in a patient with unilateral retinoblastoma that had failed prior intra-arterial chemotherapy.. Oral administration of digoxin produced no effect, while intra-arterial digoxin therapy produced a modest but measurable response that was likely limited by the inability to achieve sustained drug concentration in the eye.. This case highlights both the potential promise and limitations of cardiac glycoside therapy in retinoblastoma.

Topics: Administration, Oral; Antineoplastic Agents; Cardiotonic Agents; Child, Preschool; Digoxin; Eye Enucleation; Humans; Infusions, Intra-Arterial; Male; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma