EFFECT OF HYPERTHERMIA ON THE CYTOTOXICITY OF 2',2'-DIFLUORODEOXYCYTIDINE (GEMCITABINE) IN CULTURED SW1573 CELLS

Difluorodeoxycitidine (dFdCyd, gemcitabine) was tested for cytotoxicit y in cultured human lung-cancer cells SW1573 in combination with I hr hyperthermia at 43 degrees C. The results show that the timing is extr emely important. Simultaneous application led to decreased cytotoxicit y, whereas an interval of 20 or 24 hr between exposure to dFdCyd and h yperthermia led to enhanced cell killing. The decrease in cytotoxicity after simultaneous hyperthermia and dFdCyd probably results from inhi bition of activation of dFdCyd to the triphosphate metabolite. The enh anced cytotoxicity in sequential application of dFdCyd and hyperthermi a is not caused by accumulation of cells in a sensitive cell-cycle pha se. Our results show that the GI phase becomes relatively abundant 20 hr after exposure to 0.1 mu M dFdCyd, approximately 48% verses 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 X 10(5) cells per dish than at 400 cells per dish. This reutilization of activated drug is evidently not a restricted property of a particular cell line and may add to th e value of the drug in cancer treatment. (C) 1995 Wiley-Liss, Inc.