Effect of hyperthermia on the cytotoxicity of 2′,2′‐difluorodeoxycytidine (gemcitabine) in cultured SW1573 cells

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Abstract
Difluorodeoxycitidine (dFdCyd, gemcitabine) was tested for cytotoxicity in cultured human lung‐cancer cells SW1573 in combination with 1 hr hyperthermia at 43°C. The results show that the timing is extremely important. Simultaneous application led to decreased cytotoxicity, whereas an interval of 20 or 24 hr between exposure to dFdCyd and hyperthermia led to enhanced cell killing. The decrease in cytotoxicity after simultaneous hyperthermia and dFdCyd probably results from inhibition of activation of dFdCyd to the triphosphate metabolite. The enhanced cytotoxicity in sequential application of dFdCyd and hyperthermia is not caused by accumulation of cells in a sensitive cell‐cycle phase. Our results show that the G1 phase becomes relatively abundant 20 hr after exposure to 0.1 μM dFdCyd, approximately 48% versus 31% in control cultures. Presumably,. inhibition by hyperthermia of repair of DNA damage plays a role. Our results confirm earlier data with regard to reutilization of activated dFdCyd at high cell density. dFdCyd was clearly more toxic to SW1573 cells at 4 × 105 cells per dish than at 400 cells per dish. This reutilization of activated drug is evidently not a restricted property of a particular cell fine and may add to the value of the drug in cancer treatment.