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Cell Killing and Sensitization to Heat Shock by Hypothermic Incubation of Asynchronous and Synchronized Mouse Neuroblastoma Cells

Department of Molecular Cell Biology, University of Utrecht, Padualaan 8, 3584 CH Utrecht [G. v. D., G. Z., R. v. W.], and Department of Radiotherapy, Academic Hospital, Free University of Amsterdam, Amsterdam [J. v. R.], The Netherlands

The effect of hypothermia on cell survival and on subsequent response to hyperthermia was studied in asynchronous and synchronized Neuro-2A cells. Cell cycle progression was blocked at temperatures below 27°C. Immediately after shift to hypothermic temperatures, cells became more sensitive to hyperthermia. Development of thermosensitization was time and temperature dependent. Thermosensitization of cells by hypothermia was high at 0°C and 15°–30°C and less at 5°–10°C. Sensitization started to occur before hypothermic cell death became manifest and developed gradually. Hypothermic cell death was observed when the cells were incubated for more than 1 day at temperatures of 0°–24°C with a minimal cell death during incubation at 6°C. Thermosensitization of cells by hypothermia depended on the position of the cell in the cell cycle at the time of shift to hypothermic temperatures. Cells in late G₁ and early S phase became more thermosensitive than did cells in G₁ or late S-G₂ phase. Furthermore G₁-S cells were more sensitive to prolonged hypothermia alone than were G₁ or late S-G₂ cells. In contrast, late S-G₂ cells were most sensitive to hyperthermia alone. It is concluded that the temperature- and cell cycle-dependent way of hypothermic induced cell death was similar to the thermosensitization of cells by hypothermia. But thermosensitization became manifest prior to the actual cell death, following hypothermic treatment.

¹ To whom requests for reprints should be addressed.

Received 12/26/84. Revised 5/10/85. Accepted 5/16/85.