The topoisomerase I inhibitors, camptothecin and beta-lapachone, induce apoptosis of human retinal pigment epithelial cells

The aim of the study was to determine whether the topoisomerase I inhibitor s, camptothecin and beta-lapachone, are suitable agents for the adjuvant ph armacotherapy of proliferative vitreoretinopathy (PVR). The effects of the drugs on cultured human retinal pigment epithelial (RPE) cells were examine d using growth assays, cytotoxicity assays, single cell agarose gel electro phoresis, in situ DNA end labeling and immunoblot analysis for apoptosis-re gulatory proteins. Both agents killed RPE cells in a concentration- and tim e-dependent manner. Cell death was apoptotic as assessed by single cell aga rose gel electrophoresis and in situ DNA end labeling. Camptothecin, but no t beta-lapachone, induced accumulation of p53 and the major growth arrest-a ssociated p53 response protein, p21. Both drugs enhanced expression of the proapoptotic BAX protein. Camptothecin, but not beta-lapachone, synergistic ally enhanced RPE cell apoptosis induced by the cytotoxic cytokine, CD95 li gand (CD95L). This effect was linked to camptothecin-induced inhibition of RNA synthesis. Atypical topoisomerase I inhibitors may be promising agents for the adjuvant pharmacotherapy of PVR. Experimental studies to assess pos sible ocular toxicity upon local administration and to confirm its therapeu tic efficacy in an animal model of PVR are required. (C) 1998 Academic Pres s.