title: Lack of cell-cycle specific effects of tumor necrosis factor-alpha on tumor cells in vitro: implications for combination tumor therapy with doxorubicin.
abstract: Addition of tumor necrosis factor-alpha (TNF-alpha) to chemotherapy enhances tumor response in several treatment modalities. However, it has been shown that TNF-alpha, and several other cytokines, exert inhibitory effects on cell-cycle progression and by doing so may attenuate sensitivity of these cells to cell-cycle dependent cytotoxic drugs (e.g., doxorubicin). Here, we determined the cytotoxic effect of TNF-alpha on several tumor cell lines in vitro in combination with doxorubicin (cell-cycle dependent) or melphalan (cell-cycle independent), and its effect on cell-cycle progression. The rat cell lines were prepared from tumors, which were used previously in animal studies, in which synergy was shown between TNF-alpha and the cytotoxic drugs. Results demonstrate that the addition of TNF-alpha to doxorubicin or melphalan in vitro had no attenuating effect on the cytotoxic drugs. Depending on the cell type used, addition of TNF-alpha induced no or only an additive cytotoxic effect. Only the tested rat osteosarcoma tumor cells demonstrated a cell arrest in the G2 phase, which did not result in attenuation of the cytotoxicity of doxorubicin towards these cells.
authors.affiliation: Laboratory for Experimental Surgical Oncology, Room Ee 0102a, Department of Surgical Oncology, University Hospital Rotterdam-Dijkzigt/Daniel Den Hoed Cancer Center, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: van der Veen
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D008558:Melphalan