Sensitivity of tumour cells to heat and ways of modifying the response.

In our view, the initial effect of hyperthermia on cells is the disorganization of the membrane lipid. Such disorganization alters the membrane's biophysical properties leading to passive changes in transmembrane permeability, shifts in surface charge, and altered stereoorganization of macromolecules associated with the membrane. For example, the passive permeability changes could account for the observed increase in the association of non-histone proteins to chromatin. Surface charge changes resulting from relative changes in the phospholipids could shift the concentration and types of membrane-bound proteins. Such events could initiate hyperthermic cell death. Membranes of tumour cells are characterized by elevated cholesterol. Such differences in cholesterol concentration with their attendant shift of biophysical characteristics could explain the variation in heat sensitivity between cell lines and within the cell cycle. Further support for lipids being the initial target comes from our studies demonstrating enhanced thermosensitivity when anaesthetics are present. Thermosensitivity of solid tumours is not further influenced by lidocaine in host animals fed diets enriched in linoleic acid, a diet which markedly modifies fatty acid, phospholipid patterns and cholesterol concentration of cellular membranes. One should recognize that global measures of change, such as the ratio of unsaturated to saturated fatty acids, in unsaturated fatty acid index, or percentage of unsaturated fatty acids, may not accurately reflect changes in fatty acid patterns which are related to changes in thermosensitivity. For example, we now recognize that double bond location with respect to the headgroup must be considered as well as the relative content of unsaturated fatty acids in the membrane. Further studies bearing on the role of diet and anaesthetics on cell killing and on metastatic spread are needed. An increased understanding of the relationship of membrane biophysics and biochemistry correlated with how cells respond to heat could aid in elucidating the mechanisms of cell death. Such knowledge could provide a more rational basis for cancer therapy. The association between pyrexia and tumour regression was noted as early as 1866 by Busch who observed neoplasm remission in patients afflicted with severe erysipelas (Busch, 1866). Over the past 80 years clinicians have on occasion treated tumours by heat alone or, more recently, in combination with radiotherapy (Dickson, 1979; Jensen, 1903).(ABSTRACT TRUNCATED AT 400 WORDS)