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Most tumors, including gliomas, are resistant to tumor necrosis factor (TNF) cytotoxicity unless protein or RNA synthesis is inhibited. We investigated the effects of the combined use of TNF-α and cisplatin (CDDP) on cultured malignant glioma cells, T98G, U373MG, A172, and U87MG. All glioma cell lines were sensitive to treatment with CDDP but resistant to TNF-α during 24 h-incubation. The combined use of CDDP and TNF-α had synergistic effects on T98G and U87MG but not on U373MG and A172 cells. Sequential treatments showed that only pretreatment with CDDP for 2 h followed by TNF-α for 22 h was synergistic on cell cytotoxicity. Annexin V-flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling assay showed that TNF-α can induce apoptosis in cells treated with CDDP. Although only sensitive cell lines express transcripts for p75 TNF receptor 2, changes in TNF receptors were not found to contribute to the susceptibility to TNF-α. The production of interleukin-6, a representative cytoprotective cytokine, from glioma cells stimulated by TNF-α was suppressed by the combined use of actinomycin D, but not CDDP. Our results indicate that CDDP can sensitize glioma cells to TNF-α-induced apoptosis by a mechanism other than blocking the cytoprotective protein production.