Abstract
Purpose :
Proliferative vitreoretinopathy (PVR) is a sight-threatening complication of retinal detachment and its surgical repair with no effective treatment. The aim of this study is to identify promising drug combinations with a potential synergistic effect by carrying out a screen in our primary culture model and an explant model of PVR.
Methods :
Twelve candidate drugs were tested at 2 concentrations at 72 hours for their effects on proliferation and cytotoxicity in C-PVR cells. The most significant hits were tested in combination with other compounds to study combinatorial effects on proliferation. This effect was further evaluated in an ex vivo explant model, and total branch lengths were measured.
Results :
At 5 μM concentration 6 out of 12 drugs, bendamustine, semagacestat, daclatsvir, marbofloxacin, stavudine, and resveratrol significantly inhibited cell proliferation (20%, 30%, 16%, 30%, 19%, and 28% inhibition respectively). At 1 μM concentration, 2 out of 12 drugs, bendamustine (25%) and semagacestat (28%) significantly inhibited proliferation. 30 μM melphalan induced 74% inhibition, and a 60 μM concentration reduced cell proliferation by 83%. Topotecan at 40 nM induced a 54% decrease in proliferation, and a 53% decrease was noted with 80 nM. Daunorubicin, 15 nM treatment resulted in a 50% reduction, while the 30 nM treatment resulted in a 53% reduction in proliferation. Likewise, with lenalidomide, 24% inhibition of proliferation was observed. The combination of melphalan or topotecan with other drugs showed a dramatic effect on the proliferation of C-PVR cells. Melphalan showed synergistic effect with all 10 drugs. In comparison, with topotecan, 6 out of 10 showed a synergistic effect in combination. No significant cell death was observed. Melphalan at 30 μM (27.5 mm total branch length) and topotecan at 40 nM (34 mm total branch length) alone reduced the distance covered by outgrowths compared to vehicle (167 mm total branch length) in the explants. Explants treated with combination therapy showed an almost complete inhibition of any growth suggesting synergistic effect.
Conclusions :
The majority of our candidate drugs showed dose dependent effects on C-PVR cell proliferation. Melphalan and topotecan in combination with other drugs successfully inhibited proliferation in vitro, and in an explant model of PVR suggesting synergistic effects of these agents when used as combination therapy.
This is a 2021 ARVO Annual Meeting abstract.