Enhancement of Cytotoxicity of Cisplatin in vitro by Recombinant Human Tumor Necrosis Factor and/or Recombinant Human Interferon‐α, β and ‐γ

This study was conducted to investigate the modulatory effects of recombinant human tumor necrosis factor (rH‐TNF) and recombinant human interferon (rH‐IFN)‐α, ‐β and ‐γ, either alone or in combination, on the cytotoxicity of cisplatin, using MTT assay, against MKN‐45 (human stomach adenocarcinoma). MKN‐45 was resistant to rH‐TNF even at doses up to 10(3) U/ml. rH‐IFN‐γ inhibited the survival of MKN‐45 dose‐dependently, while rH‐IFN‐α and ‐β did not inhibit the survival of MKN‐45 even at the highest concentrations tested (10(4) U/ml). Combination of rH‐TNF with rH‐IFN‐α, ‐β or ‐γ did not significantly inhibit the survival of MKN‐45, except for a combination of 10 U/ral of rH‐TNF and 10(3) U/ml of rH‐IFN‐γ (P<0.05). Cisplatin inhibited the survival of MKN‐45 dose‐dependently. By the simultaneous combination of cisplatin with rH‐TNF and/or rH‐IFN‐α, ‐β or γ, cytotoxicity of cisplatin was enhanced and the combination effects were additive. The effects of rH‐TNF and rH‐IFN‐α, β and ‐γ on the modification of cytotoxicity of cisplatin were evaluated in terms of modification index (MI), demonstrating that rH‐TNF, rH‐IFN‐α, ‐β and ‐γ all augmented the cytotoxicity of cisplatin: MI values at 10(3) U/ml of rH‐IFN‐α, ‐β and ‐γ were 1.4, 1.4 and 2.3, respectively; those at the same concentrations of rH‐IFN‐α, ‐β and ‐γ in the presence of 10 U/ml of rH‐TNF were 3.6, 2.5 and 5.1, respectively. These results demonstrating that the cytotoxicity of cisplatin was enhanced by rH‐TNF and/or rH‐IFN‐α, ‐β or ‐γ suggest that cancer may be more effectively treated with the combination of cisplatin with these biological response modifiers than with cisplatin alone.