The relevance of tumour pH to the treatment of malignant disease

Wike-Hooley, Jennifer L.; Haveman, J.; Reinhold, H

doi:10.1016/s0167-8140(84)80077-8

Cited by 845 publications

(477 citation statements)

References 76 publications

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“…The pHe of most tumours in vivo is within the range 6.6-7.4 (Wike-Hooley et al, 1984;Tannock and Rotin, 1989;Vaupel et al, 1989). Experimental studies have suggested that the energy status is particularly low in hypoxic tumour cells at PHe in the lower part of this range, because of inhibited glycolysis owing to the low PHe (Halperin et al, 1969;Rotin et al, 1986;Casciari et al, 1992;Gerweck et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Many tumours develop hypoxic regions and regions with low extracellular pH (pHe) during growth (Wike-Hooley et al, 1984;Stone et al, 1993). Two types of hypoxia have been recognized in tumours: chronic hypoxia, resulting from limitations in oxygen diffusion; and acute hypoxia, resulting from transient cessations in blood flow (Horsman, 1995).…”

mentioning

confidence: 99%

“…Low PHe in tumours is mainly a result of increased rate of glycolysis and poor vascularization, leading to inadequate removal of H+ (Vaupel et al, 1989). The rate of glycolysis is up-regulated in hypoxic tumour cells (Robin et al, 1984), and as anaerobic glycolysis leads to accumulation of lactic acid (Busa and Nuccitelli, 1984;Wike-Hooley et al, 1984;Vaupel et al, 1989) the PHe might be particularly low in the hypoxic regions of tumours (Kallinowski and Vaupel, 1988;Tannock and Rotin, 1989;Martin and Jain, 1994).…”

mentioning

confidence: 99%

“…Tumour treatment response depends on the metabolic microenvironment of the tumour cells (Wike-Hooley et al, 1984;Sutherland et al, 1988). Hypoxic tumour cells are resistant to radiation therapy (Coleman, 1988) and some forms of chemotherapy (Teicher, 1994).…”

mentioning

confidence: 99%

“…Cell cultures of four human melanoma lines were exposed to hypoxia in vitro at pHe 7.4, 7.0 or 6.6, and adenylate energy charge was measured as a function of exposure time. As glucose is the main energy source of tumour cells under hypoxic conditions (Wike-Hooley et al, 1984;Vaupel et al, 1989), the rates of glucose uptake and lactate release were used as measures of energy generation.…”

mentioning

confidence: 99%

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Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro

Skøyum

Eide²,

Berg³

et al. 1997

Br J Cancer

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Summary The response to treatment and the malignant progression of tumours are influenced by the ability of the tumour cells to withstand severe energy deprivation during prolonged exposure to hypoxia at normal or low extracellular pH (pHe). The objective of the present work was to demonstrate intertumour heterogeneity under conditions of microenvironment-induced energy deprivation and to investigate whether the heterogeneity can be attributed to differences in the capacity of the tumour cells to generate energy in an oxygen-deficient microenvironment. Cultures of four human melanoma cell lines (BEX-c, COX-c, SAX-c, WIX-c) were exposed to hypoxia in vitro at PHe 7.4, 7.0 or 6.6 for times up to 31 h by using the steel-chamber method. High-performance liquid chromatography was used to assess adenylate energy charge as a function of exposure time. Cellular rates of glucose uptake and lactate release were determined by using standard enzymatic test kits. The adenylate energy charge decreased with time under hypoxia in all cell lines. The decrease was most pronounced shortly after the treatment had been initiated and then tapered off. BEX-c and SAX-c showed a significantly higher adenylate energy charge under hypoxic conditions than did COX-c and WIX-c whether the PHe was 7.4, 7.0 or 6.6, showing that tumours can differ in the ability to avoid energy deprivation during microenvironmental stress. There was no correlation between the adenylate energy charge and the rates of glucose uptake and lactate release. Intertumour heterogeneity in the ability to withstand energy deprivation in an oxygen-deficient microenvironment cannot therefore be attributed mainly to differences in the capacity of the tumour cells to generate energy by anaerobic metabolism. The data presented here suggest that the heterogeneity is rather caused by differences in the capacity of the tumour cells to reduce the rate of energy consumption when exposed to hypoxia.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro

Skøyum

Eide²,

Berg³

et al. 1997

Br J Cancer

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Increased hyaluronidase levels in breast tumor metastases

Bertrand¹,

Girard²,

Duval³

et al. 1997

Int. J. Cancer

126

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Thermotolerance and intracellular pH in two Chinese hamster cell lines adapted to growth at low pH

et al. 1996

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As an in vitro model for the low extracellular pH (pHe) which has frequently been observed in tumors, cell lines have been grown in a low-pH medium in order to allow cell adaptation to that milieu. Two Chinese hamster cell lines [Chinese hamster ovary (CHO) and Chinese hamster ovarian carcinoma (OvCa)] were compared, both of which acquired thermotolerance during 42 degrees C heating in pHe = 7.3 buffer, but not in pHe = 6.7 medium unless grown at that pH long enough to become adapted. CHO cells, even when acutely acidified, showed higher intracellular pH (pHi) values in a suspension assay than OvCa cells, which confirmed the danger of comparing absolute values of pHi between cell lines. Despite this fundamental difference, relative changes in pHi were similar in that both lines showed a higher pHi in adapted than in unadapted cells, over the range of pHe values tested. The upregulation of pHi was statistically significant, but the two lines differed in the time frame over which adaptation occurred. OvCa cells acquired an enhanced ability to develop tolerance to 42 degrees heat at pHe = 6.7 in 4 days, but the CHO cells acquired this ability more progressively, achieving a maximum ability at approximately 100 days. In contrast, both lines were able to upregulate their pHi within 4 hours of being exposed to pH 6.7 medium. A further indication of different biochemical mechanisms at work was the opposite effects seen on pHi in the two cell lines upon the removal of extracellular CO2/HCO3-. The differential between adapted and unadapted OvCa cells was enhanced by removal of bicarbonate, whereas CHO cells seemed less stable and the data with greater scatter failed to show any difference between adapted and unadapted cells.

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The relevance of tumour pH to the treatment of malignant disease

Cited by 845 publications

References 76 publications

Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro

Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro

Increased hyaluronidase levels in breast tumor metastases

Thermotolerance and intracellular pH in two Chinese hamster cell lines adapted to growth at low pH

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