The mode and kinetics of cell killing in HeLa and L5178Y cells were investigated to elucidate possible relationships between the mechanisms and modes of heat-induced cell death. L5178Y cells were heat-shocked for either 24 min at 43 degrees C or 30 min at 45 degrees C, while HeLa cells were given only the latter treatment. The degree of heat-induced excess nuclear protein correlated with cell death in HeLa cells but not in L5178Y cells. This difference suggests that the mechanism of cell death differs between these cell lines. With L5178Y cells the main mode of death after treatment at 43 degrees C was apoptosis with little progression of cells through the cell cycle. However, after treatment at 45 degrees C these cells died by necrosis without progressing through the cell cycle. HeLa cells were found to die by a mechanism other than apoptosis after significant progression of cells through the cell cycle and perturbation of the normal distribution of cells in the phases of the cell cycle (specifically, the fraction of cells in S and G2 phase increased 50% and 30%, respectively, prior to the occurrence of measurable cell death). These results are consistent with the hypothesis that the response to injury which has the potential to be lethal varies between different cell types, and results in the induction of different pathways leading to cell death.