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C Heinz, T Hudde, K Heise, KP Steuhl; Mycophenolate Mofetil Inhibits Human Tenon Fibroblast Proliferation by Guanosine Depletion . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3342.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mycophenolate mofetil (MMF) inhibits proliferation of lymphocytes by blocking the inosine monophosphate dehydrogenase which leads to depletion of guanosine and consequently inhibition of DNA replication. In many other cells a salvage pathway exists to produce guanosine. Long term success of glaucoma filtering surgery depends on the wound healing response of human Tenon fibroblasts (HTF). In previous experiments we demonstrated that long term exposure to MMF has an antiproliferative effect on HTF in vitro. In this set of experiments we investigated if MMF incubation for only 10 minutes leads to growth inhibition of HTF and if guanosine substitution antagonises this effect. Methods: HTF (passage 3-7) were grown in DMEM culture medium supplemented with 10% fetal calf serum in 96 well plates. Guanosine was added with or without MMF to HTF. Proliferation was assessed at days 7, 14 and 21 by cell counts. MMF was added at concentrations ranging from 100 µM to 3000 µM. After 10 minutes culture plates were washed twice with PBS and culture medium was added. Cell counts were performed at day 7 and 14. Necrotic cells were stained with tryphane blue in all experiments. Results: HTF incubated with guanosine alone and in combination with MMF showed normal proliferation as did the control group. HTF showed total growth inhibition after exposure to MMF for only 10 minutes. Concentrations higher than 300 µM of MMF did not show any proliferation during the following 7 days. When incubated for 14 days a total growth inhibition could only be observed with concentrations of 1000 µM or higher. None concentration of MMF showed morphologic changes assessed by phasecontrast microscopy. Conclusion: MMF inhibits HTF proliferation by guanosine depletion. A sufficient salvage pathway does not exist. Brief exposure to MMF leads to growth inhibition. The effect is concentration dependent. MMF could be a useful antiproliferative drug in glaucoma filtering surgery.
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