Synergistic effect and possible mechanisms of tumor necrosis factor and cisplatin cytotoxicity under moderate hyperthermia against gastric cancer cells

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Abstract
Background: Peritoneal carcinomatosis is a difficult management problem, and intraperitoneal treatment approaches may provide an opportunity to intensify dose and minimize toxicity. The current experiments were conducted to characterize the cytotoxic effects of cisplatin (cDDP), tumor necrosis factor (TNF), and hyperthermia (HT) on a gastric cancer cell line in vitro under conditions achievable with intraperitoneal treatment. Methods: Seoul National University gastric cancer cell line (SNU-5), a poorly differentiated gastric cancer cell line, was tested for sensitivity to various doses of cDDP, TNF, or combinations of the two at normothermia (37°C) or HT (42.5°C). The effect of TNF on cellular rates of cDDP accumulation, efflux, and cDDP-DNA adduct formation were evaluated using atomic absorbance spectrometry with Zeemen background correction. Results: During a 2-h exposure to various doses of cDDP with HT, we observed a supraadditive cytotoxicity of SNU-5 with 1 to 50 µg/ml of TNF (p2=0.0001). In the presence of the three-agent combination (HT, TNF, and cDDP) we observed statistically significant increases in total cellular accumulation of cisplatin (p2=0.016); a nonsignificant decrease in cellular efflux of drug (p2=0.098); and a 40% increase in persistent cisplatin DNA damage as measured by atomic absorption spectrophotometry (p2=0.06). These patterns were specifically not seen with the combinations of cDDP and HT, or cDDP and TNF. Conclusions: These data provide the experimental basis for the use of TNF and cDDP with HT in the treatment of gastric cancer and support the investigation of these agents in vivo in the regional treatment of peritoneal carcinomatosis.