HUMAN TUMOR EXTRACELLULAR PH AS A FUNCTION OF BLOOD-GLUCOSE CONCENTRATION
HUMAN TUMOR EXTRACELLULAR PH AS A FUNCTION OF BLOOD-GLUCOSE CONCENTRATION
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DOI：
10.1016/0360-3016(94)90114-7
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发表时间：
1994-03-01
影响因子：
7
通讯作者：
TUPCHONG, L
中科院分区：
文献类型：
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作者：
LEEPER, DB;ENGIN, K;TUPCHONG, L
目的：当细胞外pH(pH(E))急剧降低到pH 7.0-7.2时，哺乳动物细胞对高温敏感。然而，长期适应低pH(E)的细胞可能不会表现出这种敏感性。尽管人类肿瘤的大部分细胞外环境处于低于正常生理pH的水平，但可能有必要对肿瘤进行剧烈酸化，以改变对高温的治疗反应。本研究的目的是通过升高血糖来降低人体肿瘤细胞外pH。方法和材料：对25例空腹、非糖尿病患者口服100g葡萄糖后，肿瘤pH(E)的变化作为血糖浓度变化的函数进行测量。PH(E)用针状微电极测定，血糖用‘’Chemstrips‘’和血糖仪测定。部分患者服药后血糖浓度随时间延长而升高，30~70min达到峰值50~100 mg/dL，随后开始下降。结果：在14例(56%)一过性高血糖患者中，随着血糖升高，肿瘤组织pH平均下降-0.17+/-0.04pH单位(p<或等于-0.0001，范围-0.41-+0.07)。相比之下，在8名持续性高血糖患者中，肿瘤pH(E)保持不变或实际上增加了0.03+/-0.04个pH单位(范围为-0.15-0.14)。5例患者的正常组织pH(E)因高血糖而无变化，pH(E)=7.33+/-0.03。在所有患者中，52%的患者pH(E)下降大于或等于0.1pH单位，24%的患者pH(E)下降大于或等于0.2pH单位。5例糖前肿瘤pH(E)在6.90~7.22之间的一过性高血糖患者，高血糖引起的pH(E)平均下降0.25+/-0.05个pH单位。PH(E)的变化与血糖的最大变化呈线性关系，当血糖变化最小时，肿瘤的pH(E)下降幅度最大。斜率为0.0017+/-0.0005个pH单位/mg/dL葡萄糖(p<或等于-0.005)。这种线性关系包括短暂性高血糖患者和持续性高血糖患者。结论：由于血糖变化最小的患者肿瘤pH(E)下降最大，这可能是因为这些患者的细胞有更好的细胞内葡萄糖转运能力，而肿瘤细胞可以更快地从有氧和/或无氧糖酵解中产生乳酸。这些数据可能有助于预测个体患者对作为临床热敏剂的口服高血糖的反应。
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.