Effects of etoposide (vp16) on vertebrate retinal function

Etoposide (VP16), a clinically available anticancer compound known as a pot ent inhibitor of topoisomer ase II, was demonstrated to inhibit irreversibl y cytomegalovirus (CMV) replication. This study was performed to evaluate n ontoxic concentrations of etoposide for intravitreal injection and vitrecto my infusion in patients with CMV retinitis. We used the isolated perfused v ertebrate retina technique, an electrophysiological in vitro technique, for examination of retinal toxicity in higher vertebrates. Bovine and human re tina preparations were perfused with an oxygen-preequilibrated standard sol ution. The electroretinogram (ERG) was recorded as transretinal potential u sing AgAgCl electrodes. The ERG serves as an indicator of the integrity of the photoreceptors, the first retinal synapse, and higher retinal neurons. After recording of stable ERG amplitudes, the drug was added to the solutio n for 45 min in the following concentrations: 0.0063, 0.021, 0.063, 021,mMo l/L. The preparation was then reperfused with standard solution for another 45 min. The percentage of b-wave reduction after exposure was calculated. Toxic effects of etoposide were found for concentrations of 0.063 mMol/L (3 7.5 mu g/ml) or higher. The effects after application of the higher concent rations were not reversible within the recovery time. Examination of a few isolated human retina preparations showed similar results. The ERG reflecti ng first- and higher-order neuron activity of the retina showed toxic effec ts only at concentrations distinctly exceeding the etoposide concentration found to inhibit irreversibly CMV replication in vitro (2.5 mu g/ml). Intra vitreal injections of etoposide with due consideration of the therapeutic i ndex may provide a safe and effective means of treatment for patients with CMV retinitis resistant to ganciclovir, foscarnet, and cidofovir.