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 inhibitors, camptothecin and beta-lapachone, are suitable agents for the adjuvant pharmacotherapy of proliferative vitreoretinopathy (PVR). The effects of the drugs on cultured human retinal pigment epithelial (RPE) cells were examined using growth assays, cytotoxicity assays, single cell agarose gel electrophoresis, in situ DNA end labeling and immunoblot analysis for apoptosis-regulatory proteins. Both agents killed RPE cells in a concentration-and time-dependent manner. Cell death was apoptotic as assessed by single cell agarose gel electrophoresis and in situ DNA end labeling. Camptothecin, but not beta-lapachone, induced accumulation of p53 and the major growth arrest-associated p53 response protein, p21. Both drugs enhanced expression of the proapoptotic BAX protein. Camptothecin, but not beta-lapachone, synergistically enhanced RPE cell apoptosis induced by the cytotoxic cytokine, CD95 ligand (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 possible ocular toxicity upon local administration and to confirm its therapeutic efficacy in an animal model of PVR are required.
Hueber
A
A
Department of Vitreoretinal Surgery, University Eye Hospital, Cologne, Germany. arno.hueber@uni-koeln.de
Esser
P
P
Heimann
K
K
Kociok
N
N
Winter
S
S
Weller
M
M
D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy; D019014:fas Receptor / Q000378:metabolism
D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; D019014:fas Receptor; C014638:beta-lapachone; D002166:Camptothecin