HUMAN TUMOR EXTRACELLULAR PH AS A FUNCTION OF BLOOD-GLUCOSE CONCENTRATION

Purpose: Mammalian cells are sensitized to hyperthermia when the extracellular pH (pH(e)) is acutely reduced to < pH 7.0-7.2. However, cells chronically adapted to low pH(e) may not demonstrate such sensitivity. Although much of the extracellular environment of human tumors is at lower than normal physiological pH, it may be necessary to acutely acidify tumors to cause a change in the therapeutic response to hyperthermia. The purpose of this study was to reduce extracellular pH in human tumors by elevation of blood glucose. Methods and Materials: The change in tumor pH(e) was measured as a function of the change in blood glucose concentration after oral administration of 100 g glucose in 25 fasting, nondiabetic patients. pH(e) was determined by needle microelectrodes, and blood glucose determined by ''Chemstrips'' and a glucometer. In some patients blood glucose concentration rose with time after ingestion to a peak change of 50-100 mg/dL between 30-70 min and then began to decrease. In another group of patients glucose concentration increased by 100-200 mg/dL over 30-90 min and remained elevated as if the patients in this group were Type II diabetics. Results: In 14 transient hyperglycemic patients (56%), as blood glucose increased tumor pH, decreased by a mean of -0.17 +/- 0.04 pH units (p less-than-or-equal-to 0.0001, range of -0.41-+0.07). By contrast in eight persistent hyperglycemic patients, tumor pH(e) remained unchanged or actually increased an average of 0.03 +/- 0.04 pH units (range of -0.15-0.14). Normal tissue pH(e) in five patients was unchanged by hyperglycemia, pH(e) = 7.33 +/- 0.03. Among all patients, 52% exhibited a pH(e) decrease greater-than-or-equal-to 0.1 pH unit, and 24% exhibited a pH(e) decrease greater-than-or-equal-to 0.2 pH unit. In five transient hyperglycemic patients whose preglucose tumor pH(e) was between 6.90 and 7.22, the average decrease in pH(e) induced by hyperglycemia was 0.25 +/- 0.05 pH unit. A linear relationship was observed between the change of pH(e) and the maximum change in blood glucose such that the greatest decrease in tumor pH(e) occurred when the glucose change was minimal. The slope was 0.0017 +/- 0.0005 pH units/mg/dL glucose (p less-than-or-equal-to 0.005). The linear relationship included both tumors in transient hyperglycemic patients and in persistent hyperglycemic patients. Conclusion: Since patients who exhibited the lowest change in blood glucose exhibited the greatest decrease in tumor pH(e), it may be that cells in these patients were better able to transport glucose intracellularly which in tumor cells would permit a more rapid production of lactic acid from aerobic and/or anaerobic glycolysis. These data may be helpful in predicting the response of individual patients to oral hyperglycemia as a clinical thermosensitizer.