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Sabine Aisenbrey, Ulrike Hagemann, Merle Schrader, Kai Januschowski, Sven Schnichels, Daniela Suesskind; Toxic Effects of Melphalan on Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):77.
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© ARVO (1962-2015); The Authors (2016-present)
The cytostatic drug Melphalan is widely used in the treatment of retinoblastoma. Special emphasis lies on superselective intraarterial and intravitreal chemotherapy with great success regarding tumor control. Recently, clinical evidence of retinal pigment epithelial (RPE) atrophy and vascular complications after intraarterial and intravitreal application of the drug have been reported in single cases. Facing this background we investigated cellular toxic effects of Melphalan on RPE in a cell culture model.
ARPE19 cells were used after reaching 90% confluence. The effects of Melphalan (4, 10, 20, 50, 100, 166, 200 µg/ml) on cell morphology via phase contrast microscopy, proliferation using BrdU assay, cell viability via MTS assay, cell mass estimation using Crystal violet staining and apoptosis via Caspase 3/7 activity assay were examined in triplicate. Measurements were carried out after 24h of incubation time. Staurosporin and the Melphalan diluent were applied as positive and negative controls, respectively.
Morphologically increasing number and size of gaps were detectable in the cell layer with increasing Melphalan concentrations. In parallel proliferation of ARPE19 as well as their cell mass were decreasing. Cell viability was influenced by Melphalan concentrations of 50µg/ml and higher. After 24h apoptosis reached a maximum value with the 100µg/ml Melphalan concentration.
In a cell culture model using ARPE19 cells we could observe a decrease in proliferative activity, cell amount, and cell viability of RPE cells as well as an increase in apoptosis after 24h Melphalan incubation suggesting a direct toxic effect of the chemotherapeutic remedy. A direct toxic effect of Melphalan in vivo after intraarterial or intravitreal application on the RPE may be probable and may explain the clinical and angiographic alterations. Additional cytostatic drugs currently used in retinoblastoma treatment have to be investigated in this context regarding tumor control versus toxicity.
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