Enhancement of nitrocaphane cytotoxicity by hyperthermia in vitro

HEp-2 cells were treated with hyperthermia (39-44 degrees C) and nitrocaphane (NC) at various time intervals. A 1 h exposure to 39 degrees C and 41 degrees C was non-lethal to cells, but it did potentiate the cell killing of NC (1.0 micrograms/ml). It was further shown that the sequence between heat and the drug can affect cell survival. Cell killing effect was decreased when heat was given before or after administration of drug. In contrast the simultaneous administration of these two modalities was synergistic. Maximal thermotolerance of HEp-2 cells was developed using an 8-h interval at 37 degrees C between the cell exposures to two equal thermal doses (44 degrees C, 30 min). HEp-2 cells became thermotolerant when preheated for 30 min at 44 degrees C followed by a 10-h interval at 37 degrees C. The thermotolerant cells showed resistance to subsequent heat at 44 degrees C (D0 = 2.26 h, control D0 = 0.38 h), to subsequent NC treatment, and to heat combined with NC. However, in the thermotolerant cells, cytotoxicity of NC was still enhanced by hyperthermia.