INTRAVITREAL DAUNOMYCIN INDUCES MULTIDRUG-RESISTANCE IN PROLIFERATIVEVITREORETINOPATHY

PURPOSE. Adjuvant intravitreal daunomycin is frequently used for the m anagement of proliferative vitreoretinopathy (PVR). In this stud! the authors examined whether daunomycin could induce multidrug resistance (MDR), mediated by the mdr-1 gene product P-glycoprotein, in the cells responsible for reproliferation in vivo and in human retinal pigment epithelial (RPE) cells in vitro. METHODS. Expression of P-glycoprotein was examined by immunohistochemistry in surgically removed epiretinal membranes. The cellular source of P-glycoprotein was examined by cola beling for cytokeratin, dial fibrillary acidic protein, and the macrop hage marker EBM-11. P-glycoprotein expression by cultured RPE cells wa s assessed by reverse transcription-polymerase chain reaction and immu noblot analysis. Daunomycin toxicity was quantified by crystal violet assay. RESULTS. P-glycoprotein expression was detected in 10 of 10 pat ients pre-exposed to intravitreal daunomycin. In contrast. epiretinal membranes from only 2 of 13 patients never exposed to daunomycin showe d faint P-glycoprotein expression. P-glycoprotein expression was stron g within 8 months after daunomycin treatment and faded thereafter. Col ocalization studies demonstrated predominant expression of P-glycoprot ein by RPE cells. Pre-exposure of cultured human RPE cells to subtoxic concentrations of daunomycin induced resistance to daunomycin that wa s sensitive to the MDR inhibitor, verapamil. Induction of the MDR phen otype in RPE cells by daunomycin was associated with a minor increase in the mdr-1 mRNA level but a prominent increase in P-glycoprotein exp ression, thus suggesting a primarily translational mechanism of MDR de velopment in human RPE cells. CONCLUSIONS. Intravitreal daunomycin ind uced P-glycoprotein expression in PVR. Reproliferation in daunomycin-p retreated patients probably necessitates cotreatment with daunomycin a nd inhibitors of multidrug resistance such as verapamil or administrat ion of antiproliferative drugs such as 5-fluorouracil, which act in a MDR-independent fashion.