The sensitivity of a malignant cell line to hyperthermia (42°C) at low intracellular pH

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Abstract
The postulate that low intracellular pH acts as a preconditioner for the destructive effects of hyperthermia (42.degree. 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, nonmetabolizable organic acid 5,5-dimethyl-2,4-oxazolidinedione (DMO) between intracellular and extracellular H2O. Respiration, aerobic 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 or 42.degree. C over 6 h in Warburg manometers. The ability of the cells to replicate in culture was examined after 3 or 6 h incubation in the flasks. The relationship between pHi and extracellular pH (pHe) depended on the buffer system used and the exact pH in question. No assumption regarding pHi based only on pHe measurement could be made. At 38.degree. 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 was unimpaired. At 42.degree. 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.degree. C and inability to multiply following 6 h hyperthermia: low pHi did not influence these results. 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.