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Effect of Hyperthermia (45°C) on Calcium Flux in Chinese Hamster Ovary HA-1 Fibroblasts and Its Potential Role in Cytotoxicity and Heat Resistance¹

Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115 [M. A. S., S. K. C.], and Cancer Biology Research Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, California 94305 [G. M. H.]

Hyperthermia caused a major increase in uptake of ⁴⁵Ca²⁺ into Chinese hamster ovary HA-1 cells. Increased permeability to Ca²⁺ was observed with heating periods as brief as 45°C for 4 min and reached a maximum at 45°C for 30 min. In addition to elevation of Ca²⁺ influx, heat induced an increase in ⁴⁵Ca²⁺ exchange with the extracellular Ca²⁺ pool. The effect of heat on Ca²⁺ permeability was transient, and Ca²⁺ influx returned to normal values by approximately 9 h at 37°C. Comparison of the time courses of increased Ca²⁺ permeability and cell inactivation at 45°C indicated that the heating time required for maximum permeability to Ca²⁺ was similar to the initial resistant "shoulder" period of the cell survival curve. This suggests that Ca²⁺ could play a permissive role in thermal cell inactivation; efficient cell killing may require a threshold concentration of intracellular Ca²⁺. The kinetics of heat-induced increase in Ca²⁺ permeability also resembled that for the induction of thermotolerance. This might suggest a messenger role for Ca²⁺ in thermotolerance induction. Direct increase in cellular Ca²⁺ levels with Ca²⁺ ionophore A23187 (5 x 10^-6 M) led to subsequent heat resistance. However, the heat resistance produced by A23187 was of a lesser magnitude than heat-induced thermotolerance. In addition, A23187 did not induce the stress protein species characteristic of thermotolerance (heat shock proteins), but instead led to the synthesis of a related set of proteins (glucose-regulated proteins).

The data thus suggest a role for Ca²⁺ in the cellular effects of hyperthermia. They are also of potential clinical relevance in that cellular responses to heat might be modified pharmacologically, by the judicious use of Ca²⁺ active agents, such as Ca²⁺ ionophores and channel blockers.

¹ This research was supported by Grants CA 04542 and CA 32827 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 5/ 8/86. Revised 3/25/87. Accepted 4/22/87.

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