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O.R. Kayikcioglu, L. Cheng, I. Kozak, G. Bergeron–Lynn, C.T. Schulteis, F.W. Staal, N. Paoni, W.R. Freeman; Subretinal Administration of Ribozyme to the Proliferating Cell Nuclear Antigen and 5–fluorouracil in Rat Eyes . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1427.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Antiproliferative drugs may be useful in inhibiting processes associated with choroidal neovascularization and thus limiting damage in eyes with age related macular degeneration. We planned to investigate the toxicity profile of subretinal injection of ribozyme to the proliferating cell nuclear antigen (PCNA–Rz) and 5–FU, as well as to establish the highest non–toxic subretinal dose for either agent in rat eyes. Evidence shows that there is a synergistic antiproliferative effect, if a combination of both is injected. Methods: Thirty Brown Norway rats were used. Only one eye of each rat was injected with drug; the fellow eye was injected with BSS as control. PCNA–Rz at 5µg, 50µg, and 500µg in 5µl and 5–FU at 0.3, 1.5, and 7.5µg in 5µl were tested. For all drugs, each dose was tested in 5 eyes. After injection, the eyes were monitored by slit lamp, indirect ophthalmoscope and ERG examinations. Rats were sacrificed at 2 weeks, and the globes were processed for histology. Results: The highest non–toxic dose for subretinal PCNA–Rz was 50µg in 5µl. 500µg in 5µl was toxic at the injection site, showing disturbance of pigmentation at the bleb area and corresponding histological changes of retinal photoreceptor loss and retinal pigment epithelium proliferation and irregularity. Subretinal injection of all three doses of 5–FU did not show any toxicity. Even the highest dose of 7.5µg in 5µl was well tolerated in the subretinal space with normal ERG and histology. Conclusions: Subretinal PCNA–Rz of 50µg in 5µl and 5–FU dose of 7.5µg in 5µl are safe for subretinal injections in rats. Subretinal injection of a combination of the two may be non–toxic and synergistic for inhibiting subretinal proliferation associated with AMD; we are currently evaluating this combination therapy.
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