Abstract
The postulate that low intracellular pH acts as a preconditioner for the destructuve effects of hyperthermia (42 degrees C) was examined, using a heat-sensitive line of malignant cells derived from rat mammary gland (SDB). Intracellular pH (pHi) was measured indirectly, from the distribution of the weak, non-metabolizable organic acid 5,5-dimethyl-2,4-oxazolidinedione (DMO) between intra- and extra-cellular water. Respiration, aerobic and anaerobic and anaerobic glycolysis of the cells were studied at normal pHi (pH 7-0-7-4) or at low pHi (pH 6-2-6-6) and at 38 degrees C or 42 degrees C over 6 h in Warburg manometers; the ability of the cells to replicate in culture was examined after 3 h or 6 h incubation in the flasks. The relationship between pHi and extracellular pH (pHe) depended upon the buffer system used and the exact pH in question; no assumption regarding pHi based only on pHe measurement could be made. At 38 degrees C and low pHi, the Pasteur effect became negative due to a relatively greater inhibition of anaerobic than aerobic glycolysis. Respiration was unaffected and cell replicative ability unimpaired. At 42 degrees C and normal pHi, respiration was totally inhibited after 4 h and the Pasteur effect was decreased, in this case due to a compensatory increase in aerobic glycolysis without alteration in anaerobic CO2 production. Low pHi in the presence of hyperthermia enabled cell respiration to continue at a reduced level with no further change in glycolysis. There was delayed cell replication after 3 h at 42 degrees C and inability to multiply following 6 h hyperthermia: low pHi did not influence these results. It is concluded that with these cancer cells, pHi values maintained in the region of 1-0 pH unit below normal for 6 h had no deleterious effect on the cells. No sensitizing effect of the low pHi for the destructive effect of hyperthermia on the cells was observed.
Highlights
The relationship between pHi and extracellular pH depended upon the buffer system used and the exact pH in question; no assumption regarding pHi based only on pHe measurement could be made
It is concluded that with these cancer cells, pHi values maintained in the region of 1.0 pH unit below normal for 6 h had no deleterious effect on the cells
The high glycolytic rate of the cells led to a fall in pH of the Krebs-Ringer bicarbonate phosphate (KRBP) buffer over 30 min
Summary
The relationship between pHi and extracellular pH (pHe) depended upon the buffer system used and the exact pH in question; no assumption regarding pHi based only on pHe measurement could be made. The difference in heat sensitivity between cancer cells and normal cells decreases with increasing temperature above 42°C (Dickson, 1976a,b), so that temperatures in excess of this involve hazard to the host. The advantages of sensitizing the cancer cells to the effects of heat are apparent Several such preconditioners, including methylene blue, dimethylsulphate, tween 80 and glucose, have been proposed by Von Ardenne (1971). It is claimed that a high level of the sugar in the blood stimulates tumour glycolysis and selectively decreases the pH in the tumour; a difference in the region of I 0 pH unit between the cancer tissue and normal tissue enables the heating temperature to be reduced to 40TC, and at the same time there is amplification of the damaging effect of the heat on the cancer cells (Von Ardenne, 1971, 1972). Metabolism of the cells over 6 h incubation at the elevated temperature, and their subsequent replicative ability at 380C, were studied
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