VINCRISTINE-INDUCED AND CISPLATIN-INDUCED APOPTOSIS IN HUMAN RETINOBLASTOMA - POTENTIATION BY SODIUM-BUTYRATE

Chemotherapy alone has largely been unsuccessful in controlling retino blastoma growth, and has traditionally been limited in use as an alter native to irradiation for the treatment of retinoblastoma. Recently, c linical studies combining chemotherapy with local therapies, including radiotherapy, laser therapy or cryotherapy and in some cases, cyclosp orine A, have been effective in treating retinoblastoma. Differentiati ng agents may also be combined with chemotherapy to enhance the action of cytotoxic drugs on tumor cell growth, although this approach has n ot been fully investigated in retinoblastoma. In this study, we evalua ted the cytotoxic response of human retinoblastoma cell lines (Y79 and WERI-Rb1) to two chemotherapy agents commonly used in treating retino blastoma, vincristine (VCR) and cisplatin (CDDP). Retinoblastoma cells have been shown to be sensitive to the differentiating agent sodium b utyrate, and cell lines were also treated with a combination of VCR or CDDP with sodium butyrate, and the effects on retinoblastoma viabilit y assessed. Both VCR and CDDP induced dose-dependent death of Y79 and WERI-Rb1 cells, accompanied by nuclear and cytoplasmic condensation an d DNA laddering, features characteristic of apoptosis. Inhibitors of m acromolecular synthesis, cycloheximide and actinomycin-D, significantl y reduced VCR- and CDDP-induced apoptosis, although putative endonucle ase inhibitors zinc sulphate and aurintricarboxylic acid had no appare nt effect. Treatment with 0.5 mM or 1 mM sodium butyrate combined with VCR or CDDP significantly increased induction of apoptosis by these a gents. This augmentation of chemotherapy-induced apoptosis may have im plications for retinoblastoma therapy. (C) 1998 Elsevier Science Ltd. All rights reserved.