Effects of Hyperthermia on Binding, Internalization, and Degradation of Epidermal Growth Factor

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Abstract
125I-epidermal growth factor [EGF] was used as a molecular probe to study the effects of hyperthermia and local anesthetics on cultured Rat-1 [rat embryo fibroblast cells] cells. Heating cells at 45.degree. C for times up to 1 h caused a continuous decrease in EGF binding. Scatchard analysis showed that the decreased binding resulted from a decrease in the affinity of the EGF receptors rather than from a decrease in receptor number. Hyperthermia as high as 45.degree. C for 30 min did not inhibit the process of receptor-mediated endocytosis of EGF; the degradation of internalized EGF was strongly inhibited at temperatures from 43-46.degree. C. Exposure to 42.degree. C had no effect on degradation. Because EGF degradation occurs in lysosomes, the effects of heat were compared to those caused by the local anesthetics procaine and lidocaine (which prevent EGF degradation). The latter compounds, as well as other lysosomotropic amines, were similar to hyperthermia in their ability to permit accumulation of internalized EGF by preventing degradation. Because procaine and lidocaine potentiate the killing effects of hyperthermia on tumors and in cultured cells, hyperthermia and the local anesthetics may act at the same cellular site. By inhibiting the action of lysosomes, hyperthermia and local anesthetics may permit potentially toxic materials to enter the cell by endocytosis, where they would accumulate and induce lethal damage.

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