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The effects of heat shock on cell proliferation

For the past 15 years numerous studies of the effects of heat on mammalian cells have focused on cellular lethality and its modification. Such approaches were inspired by the potential application of hyperthermia to the treatment of cancer. Most clinical hyperthermia treatments attempt to heat the tumour to temperatures between 43" and 45°C for time intervals of up to 1 h. More recent clinical applications of hyperthermia involve its combination with radiotherapy and/or chemotherapy. These latter approaches present research problems which are very relevant to those of us interested in the kinetics of cell proliferation and its perturbation by therapeutic agents, since the response of a tissue to a combined therapy will often be affected by altered cell kinetics between treatments. Recent clinical approaches involving continuous heating at moderate temperatures less than 42.5"C for up to 72 h lead to another situation where the effects of heat shock on cell proliferation will be important. Clearly the efficacy of such approaches will depend upon the effects of these temperature shifts on tumour cell proliferat ion. While the cell cycle dependent variation in thermal sensitivity was documented some time ago (Westra & Dewey 1971). relatively few studies have attempted to detail alterations in cell cycle progression (Henle & Roti Roti 1988). Nevertheless. the available data suggest that heat has unique effects on the proliferation kinetics of cells and should provide interesting challenges to those with expertise in cell kinetics. Therefore, we present a review of these effects which should be of interest to the readers of Cell Proliferafion. Since one of the major effects of hyperthermia is cell killing, we must first consider the timecourse of cell death following lethal heat exposures. At least three modes of cell death can be defined. The first mode is a rapidly occurring death following heat exposures >50°C (Vidair & Dewey 1986). This type of death is not associated with cell cycle progression and is therefore of little interest from a cell kinetic point of view. The second mode occurs at intermediate heat exposures (41.5-49"C depending upon the time of exposure). For this type of cell death to be manifested it appears that it is necessary for cells to progress through S phase (Mackey & Dewey 1988). This type of cell death occurs throughout the range of hyperthermic temperatures. The third mode of cell death occurs at relatively low heat exposures at which only mitotic cells are killed (Coss & Dewey 1983). For the latter mode, progression into or through mitosis-the most heat sensitive phase of the cell cycle-is required during the period of elevated temperature prior to thermal adaptation for a lethal event to occur. Clearly, only a limited