Lack of cell-cycle specific effects of tumor necrosis factor-alpha on tumor cells in vitro: implications for combination tumor therapy with doxorubicin.

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.