INHIBITION OF CULTURED HUMAN RPE CELL-PROLIFERATION AND LYSYL HYDROXYLASE-ACTIVITY BY HYDROXY DERIVATIVES OF MINOXIDIL

Purpose. To examine the antiproliferative and lysyl hydroxylase suppre ssing effects of 3'-hydroxyminoxidil and 4'-hydroxyminoxidil, derivati ves of minoxidil devoid of the antihypertensive effect, on human retin al pigment epithelial (RPE) cells in culture. Methods, Subconfluent an d confluent cultures of RPE cells, exposed to 0.01 to 5 mM 3' or 4'-hy droxyminoxidil for 15 minutes to 7 days, were examined for proliferati on, viability, and morphologic changes. Lysyl hydroxylase activity in confluent cultures exposed to 1 mM 3'- or 4'-hydroxyminoxidil tvas det ermined by measuring the amount of (H2O)-H-3 released from L-(4,5-3(H) )lysine-labeled unhydroxylated procollagen substrate after vacuum dist illation. Results. Both compounds inhibited the proliferation of subco nfluent cultures of RPE cells in a dose-dependent fashion. The 50% eff ect occurred at 0.25 mM for 3'-hydroxyminoxidil and 0.5 mM for 4'-hydr oxyminoxidil. The antiproliferative effect was detectable within 24 ho urs, required a minimum 1-hour exposure, and persisted even after the drug was removed from the culture medium. Cell viability experiments p rovided no evidence for toxicity. In contrast, the number of cells at confluent density was not affected. Both 3'-hydroxyminoxidil and 4'-hy droxyminoxidil suppressed lysyl hydroxylase activity by 72%. Conclusio ns, The structure of minoxidil can be altered to reduce the antihypert ensive activity while preserving the antiproliferative and lysyl hydro xylase suppressing effects. The hydroxy derivatives of minoxidil may b e useful in the treatment of proliferative vitreoretinopathy, a diseas e with unwanted proliferation of RPE cells.