Effects of topoisomerase II inhibitors on retinal pigment epithelium and experimental proliferative vitreoretinopathy.
OBJECTIVE
The aim of this study was to compare the effect of several commercially available topoisomerase II inhibitors on the proliferation of retinal pigment epithelium (RPE) cells in vitro and to test the toxicity and efficacy of the inhibitor against experimental proliferative vitreoretinopathy (PVR).


METHODS
Three different topoisomerase II inhibitors (etoposide, doxorubicin, and daunorubicin) were tested in vitro. Rabbit RPE cells were cultured with or without the drugs at various concentrations. An MTT assay was used to determine the cell viability at 48 h and 96 h. Etoposide, a drug which showed a broad therapeutic range in vitro, was injected to the rabbit eye for the evaluation of the toxicity in vivo. Therapeutic effects of an intravitreal injection of etoposide were evaluated in an experimental PVR model induced by the intravitreal implantation of RPE cells in rabbits.


RESULTS
All tested topoisomerase II inhibitors showed a significant reduction of cell viability in vitro. The slope of the dose-response curve was slowly declined for etoposide, and declined sharply for doxorubicin and daunorubicin. Therefore, etoposide was selected for further toxicity and efficacy studies in vivo. There was no significant change in b-wave amplitudes in the etoposide-injected eyes (0.02 mg, 10 microg/mL) after 2 weeks, but a significant reduction occurred in the etoposide-injected eyes (0.2 mg, 100 microg/mL). In the study of the experimental model of PVR, the rabbit eyes injected with RPE cells and etoposide (0.02 mg, 10 microg/mL) showed a significantly lower grading of PVR than that of the control eyes (injected RPE cells and PBS).


CONCLUSIONS
These results indicate that etoposide would be an adjunctive for the prevention of PVR. Further pharmacokinetic study of the intravitreal injection of etoposide is required.
Kuo
Hsi-Kung
HK
Department of Ophthalmology, Chang-Gung Memorial Hospital-Kaohsiung Medical Center, and Chang-Gung University, College of Medicine, Kaohsiung, Taiwan.
Wu
Pei-Chang
PC
Yang
Po-Min
PM
Chen
Yi-Hao
YH
Wu
Yi-Chan
YC
Hu
Dan-Ning
DN
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D020714:Maximum Tolerated Dose; D010857:Pigment Epithelium of Eye / Q000187:drug effects*; D011817:Rabbits; D059005:Topoisomerase II Inhibitors; D018630:Vitreoretinopathy, Proliferative / Q000473:pathology / Q000517:prevention & control*; D014822:Vitreous Body / Q000187:drug effects*
D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D003630:Daunorubicin