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Intra- and Extracellular pH in Solid Tumors

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Antiangiogenic Agents in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

It has long been known that the interstitial environment in malignant tumors is acidic as a result of accumulation of lactic acid and other acidic metabolites. Neoplastic cells metabolize glucose preferentially through glycolysis, even in an aerobic environment resulting in the production of lactic acid (1). In solid tumors, the supply of oxygen is limited because of sluggish blood perfusion through a heterogeneously distributed vascular network, resulting in diffusion-limited hypoxia (2–5). Furthermore, it has been observed that blood perfusion through capillary-like tumor vessels often slows down, stops, or even completely reverses its direction, creating perfusion-limited hypoxia (5,6). Under such hypoxic conditions, cells metabolize glucose through anaerobic glycolysis and produce lactic acid (1, 7–9). Furthermore, a sudden induction of hypoxic condition caused by sudden cessation of blood perfusion may cause hydrolysis of ATP, resulting in the generation of H+ ions (10). For reasons unknown, small amounts of β-hydrobutyric acid were detected in experimental tumors (9). Such overproduction of acidic metabolites, notably lactic acid combined with slow discharge of the acidic metabolites via sluggish tumor blood flow, results in accumulation of acidic metabolites in the tumors. The acidic interstitial or extracellular environment in tumors inevitably influences the intracellular acidity, which in turn would exert a marked influence on the proliferation of parenchyma and endothelial cells. This chapter discusses the relationship between the extracellular and intracellular acidity in tumors, the influence of the intracellular acidity on angiogenesis, and of that on the response of tumor cells to various antineoplastic regimens.

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References

  1. Aisenberg, A. C., ed. (1961) Gycolysis and Respiration of Tumors. Academic, New York, NY.

    Google Scholar 

  2. Song, C. W. (1997) Modification of blood flow, in Blood Perfusion and Microenvironment ofHuman Tumors (Molls, M. and Vaupel, P., eds.), Springer-Verlag, Heidelberg, Germany, pp. 193–207.

    Google Scholar 

  3. Reinhold, H. S. and Endrich, B. (1986) Tumor microcirculation as a target for hyperthermia. Int. J. Hyperthermia 2, 111–137.

    Article  PubMed  CAS  Google Scholar 

  4. Jain, R. K. (1988) Determination of tumor blood flow: a review. Cancer Res. 48, 2641–2658.

    PubMed  CAS  Google Scholar 

  5. Peterson, H.-I., ed. (1978) Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow ofExperimental and Human Tumors, CRC, Boca Raton, FL.

    Google Scholar 

  6. Eddy, H. A. (1976) Microangiographic techniques in the study of normal and tumor tissue vascular systems. Microvasc. Res. 11, 391–413.

    Article  PubMed  CAS  Google Scholar 

  7. Gullino, P. M. (1975) Extracellular compartments of solid tumors, in Biology of Tumors: Cellular Biology and Growth, vol. 3, Cancer (Becker, F. F., ed.), Plenum, New York, pp. 327–354.

    Chapter  Google Scholar 

  8. Vaupel, P. W., Kallinowski, F., and Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465.

    PubMed  CAS  Google Scholar 

  9. Lee, S. Y., Ryu, K. H., Kang, M. S., and Song, C. W. (1986) Effects of hyperthermia on the lactic acid and β-hydrobutyric acid content in tumor. lnt. J. Hyperthermia 2, 213–222.

    Article  CAS  Google Scholar 

  10. Busa, W. B. and Nuccitelli, R. (1984) Metabolic regulation via intracellular pH. Am. J. Physiol. 246, R409–R438.

    Google Scholar 

  11. Cameron, J. N. (1986) pH, in Principles ofPhysiological Measurement, Academic, Orlando, FL, pp. 103–113.

    Chapter  Google Scholar 

  12. Rhee, J. G., Kim, T. H., Levitt, S. H., and Song, C. W. (1984) Changes in acidity of mouse tumors by hyperthermia. Int. J. Radiat. Oncol. Biol. Phys. 10 393–399.

    Google Scholar 

  13. Song, C. W., Kang, M. S., Rhee, J. G., and Levitt, S. H. (1980) The effect of hyperthermia on vascular function, pH and cell survival. Radiology 137, 795–803.

    PubMed  CAS  Google Scholar 

  14. Stubbs, M. (1998) Tumor pH, in Blood Perfusion and Microenvironment ofHuman Tumors (Molls, M. and Vaupel, P., eds.), Springer, Berlin, pp. 113–120.

    Google Scholar 

  15. Eden, M., Haines, B., and Kahler, H. (1955) The pH of rat tumors measured in vivo. J. Natl. Cancer Inst. 16, 541–556.

    PubMed  CAS  Google Scholar 

  16. Vaupel, P. W., Frinak, S., and Bicher, H. I. (1981) Heterogenous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res. 41, 2008–2013.

    PubMed  CAS  Google Scholar 

  17. Wike-Hooley, J. L., Haveman, J., and Reinhold, H. S. (1984) The relevance of tumour pH to the treatment of malignant disease. Radiother. Oncol. 2, 343–366.

    Article  PubMed  CAS  Google Scholar 

  18. Jahde, E., Rajewsky, M. F., and Baumgartl, H. (1982) pH distribution in transplanted neural tumors and normal tissues of BDIX rats as measured with pH microelectrodes. Cancer Res. 42, 1498–1504.

    PubMed  CAS  Google Scholar 

  19. Kallinowski, F. and Vaupel, P. W. (1988) pH distribution in spontaneous and isotransplanted rat tumors. Br. J. Cancer 58, 314–321.

    Article  PubMed  CAS  Google Scholar 

  20. Meyer, K. A., Kammerling, E. M., Amtan, L., Koller, M., and Hoffman, S. J. (1948) pH studies of malignant tissues in human being. Cancer Res. 8, 513–518.

    PubMed  CAS  Google Scholar 

  21. Pampus, F. (1963) Die Wasserstoffionenkonzentration des Hirngewebes bei raumfordernden intracraniellen Prozessen. Acta Neurochir. 11, 305–318.

    Article  PubMed  CAS  Google Scholar 

  22. Ashby, B. S. (1966) pH studies in human malignant tumours. Lancet 2, 312–315.

    Article  PubMed  CAS  Google Scholar 

  23. Thistlethwaite, A. J., Leeper, D. B., Moylan, D. J., and Nerlinger, R. E. (1985) pH distribution in human tumors. Int. J. Radiat. Oncol. Biol. Phys. 11, 1647–1652.

    Article  PubMed  CAS  Google Scholar 

  24. Wike-Hooley, J. L., van den Berg, A. P., van der Zee, J., and Reinhold, H. S. (1985) Human tumour pH and its variation. Eur. J. Cancer Clin. Oncol. 21, 785–791.

    Article  PubMed  CAS  Google Scholar 

  25. van den Berg, A. P., Wike-Hooley, J. L., van den Berg-Blok, A. E., van der Zee, J., and Reinhold, H. S. (1982) Tumour pH in human mammary carcinoma. Eur. J. Cancer Clin. Oncol. 18, 457–462.

    Article  Google Scholar 

  26. Inch, W. R. (1954) Direct current potential and pH of several varieties of skin neoplasms. Can. J. Biochem. Physiol. 32, 519–525.

    Article  PubMed  CAS  Google Scholar 

  27. Millet, H. (1923) Measurements of the pH of normal, fetal, and neoplastic tissues by means of the glass electrode. J. Biol. Chem. 78, 281–288.

    Google Scholar 

  28. Naeslund, J. and Senson, K.-E. (1953) Investigations on the pH of malignant tumours in mice and humans after the administraion of glucose. Acta Obstet. Gynecol. Scand. 32, 359–367.

    Article  CAS  Google Scholar 

  29. Vaupel, P., Kallinowski, F., and Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465.

    PubMed  CAS  Google Scholar 

  30. Griffiths, J. R. (1991) Are cancer cells acidic? Br. J. Cancer 64, 425–427.

    Article  PubMed  CAS  Google Scholar 

  31. Engin, K., Leeper, D. B., Cater, J. R., Thistlethwaite, A. J., Tupchong, L., and McFarlane, J. D. (1995) Extracellular pH distribution in human tumours. Int. J. Hyperthermia 11, 211–216.

    Article  PubMed  CAS  Google Scholar 

  32. Moon, R. B. and Richards, J. H. (1973) Determination of intracellular pH by 31P magnetic resonance. J. Biol. Chem. 248, 7276–7278.

    PubMed  CAS  Google Scholar 

  33. Stubbs, M., Bhujwalla, Z. M., Tozer, G. M., Rodrigues, L. M., Maxwell, R. J., Morgan, R., Howe, F. A., and Griffiths, J. R. (1992) An assessment of 31P MRS as a method of measuring pH in rat tumours. NMR Biomed. 5, 351–359.

    Article  PubMed  CAS  Google Scholar 

  34. Soto, G. E., Zju, Z., Evelhoch, J. L., and Ackerman, J. J. H. (1996) Tumor 31P NMR pH measurements in vivo: a comparison of inorganic phosphate and intracellular 2-deoxyglucose-6-phosphate as pHnmr indicators in murine radiation induced fibrosarcoma-1. Magn. Reson. Med. 36, 698–704.

    Article  PubMed  CAS  Google Scholar 

  35. Negendank, W. (1992) Studies of human tumors by MRS: a review. NMR Biomed. 5, 303–324. 36. Ross, B. D., Mitchell, S. L., Merkle, H., and Garwood, M. (1989) In vivo 31P and 2H NMR studies of rat brain tumor pH and blood flow during acute hyperthermia: differential effects between subcutaneous and intracerebral locations. Magn. Reson. Med. 12, 219–234.

    Google Scholar 

  36. Ackerman, J. J. H., Soto, G. E., Spees, W. M., Zju, Z., and Evelhoch, J. L. (1996) NMR chemical shift pH measurement revisited: analysis of error and modeling of a pH dependent reference. Magn. Reson. Med. 36, 674–683.

    Article  PubMed  CAS  Google Scholar 

  37. Gillies, R. J., Liu, Z., and Bhujawalla, Z. M. (1994) 31P NMR measurements of extracellular pH in situ using 3-aminopropylphosphonate. Am. J. Physiol. 267 C 195–C203.

    Google Scholar 

  38. Gillies, R. J., Raghunand, N., Bhujwalla, Z. M., Ballesteros, P., Alverez, J., and Cerdan, S. (1997) Measurement of extracellular pH in tumors by IH MRSI. Proc. Int. Soc. Magn. Reson. Med. 5, 1099 (abstract).

    Google Scholar 

  39. Metha, V. D., Kulkarni, P. V., Mason, R. P., Constantinescu, A., Aravind, S., Goomer, N., and Antich, P. P. (1994) 6-Fluoropyridoxol: A novel probe ofcellularpH using 19F NMR spectroscopy.FEBS Letter, 349, 234–238.

    Article  Google Scholar 

  40. Daly, P. F. and Cohen, J. S. (1989) Magnetic resonance spectroscopy of tumors and potential in vivo clinical applications: a review. Cancer Res. 49, 770–779.

    PubMed  CAS  Google Scholar 

  41. Bottomley, P. A. (1989) Human in vivo NMR spectroscopy in diagnostic medicine: clinical tool or research probe? Radiology 170, 1–15.

    PubMed  CAS  Google Scholar 

  42. Roos, A. and Boron, W. F. (1981) Intracellular pH. Physiol. Rev. 61, 296–434.

    PubMed  CAS  Google Scholar 

  43. Madshus, I. H. (1988) Regulation of intracellular pH in eukaryotic cells. J. Biochem. 250, 1–8.

    CAS  Google Scholar 

  44. Grinstein, S. and Rothstein, A. (1986) Mechanisms of regulation of the Na+/H+ exchanger. J. Membrane Biol. 90, 1–12.

    Article  CAS  Google Scholar 

  45. Frelin, C., Vigne, P., Ladoux, A., and Lazdunski, M. (1988) The regulation ofthe intracellularpH in cells from vertebrates. Eur. J. Biochem. 174, 3–14.

    Article  PubMed  CAS  Google Scholar 

  46. Aronson, P. S. (1985) Kinetic properties of the plasma membrane Na+/H+ exchange. Annu. Rev. Physiol. 47, 545–560.

    Article  PubMed  CAS  Google Scholar 

  47. Scholz, W., Albus, U., Counillon, L., Gogelein, H., Lang, H. J., Linz, W., Weichert, A., and Scholkens, B. A. (1995) Protective effects of HOE642, a selective sodium–hydrogen exchange subtype 1 inhibitor, on cardiac ischemia and reperfusion. Cardiovascular Res. 29, 260–268.

    Google Scholar 

  48. Cassel, D., Katz, M., and Rotman, M. (1986) Depletion of cellular ATP inhibits Na+/H+ antiport in cultured human cells. Modulation of the regulatory effect of intracellular protons on the antiporter activity. J. Biol. Chem. 261, 5460–5466.

    PubMed  CAS  Google Scholar 

  49. Zhung, Y. X., Cragoe, E. J., Jr., Glaser, L., and Cassel, D. (1984) Characterization of potent Na+/H+ exchange inhibitor from the amiloride series in A43l cells. Biochemistry 23, 4481–4488.

    Article  Google Scholar 

  50. Kim, G. E., Song, C. W., Lyons, J. C., and Rhee, J. G. (1988) Modifying effect of amiloride on thermotolerance of mouse mammary carcinoma cells in vitro. Int. J. Radiat. Oncol. Biol. Phys. 15, 175 (abstract).

    Google Scholar 

  51. Lyons, J.C., Kim, G. E., and Song, C. W. (1992) Modification of intracellular pH and thermosensitivity. Radiat. Res. 79, 79–87.

    Article  Google Scholar 

  52. Song, C. W., Lyons, J. C., Griffin, R. J., Makepeace, C. M., and Cragoe, E. J., Jr. (1993) Increase in thermosensitivity of tumor cells by lowering intracellular pH. Cancer Res. 53, 1599–1601.

    PubMed  CAS  Google Scholar 

  53. Cassel, D., Scharf, O., Rotman, M., Cragoe, E. J., Jr., and Katz, M. (1988) Characterization ofNa+_linked and Na+-independent CI-/HCO3 exchange systems in Chinese hamster lung fibroblasts. J. Biol. Chem. 263, 6122–6127.

    PubMed  CAS  Google Scholar 

  54. Boron, W. F. (1986) Intracellular pH regulation in epithelial cells. Am. Rev. Physiol. 48, 377–388.

    Article  CAS  Google Scholar 

  55. Hutton, J. C. (1982) The internal pH and membrane potential ofthe insulin-secretory granule. J. Biochem. 204, 171–178.

    CAS  Google Scholar 

  56. Thomas, R. C. (1976) Ionic mechanism of the H+ pump in a snail neuron. Nature 262, 54–55.

    Article  PubMed  CAS  Google Scholar 

  57. Russell, J. M. and Boron, W. F. (1976) Role ofchloride transport in regulation of intracellularpH. Nature 264, 73,74.

    Google Scholar 

  58. Boron, W. F., Hogan, E., and Russell, J. M. (1988) pH-sensitive acidification of the intracellular-pH regulation system in squid axons by ATP-a-s. Nature 332, 262–265.

    Google Scholar 

  59. Belt, J. A., Thomas, J. A., Buchsbaum, R. N., and Racker, E. (1979) Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavanoids. Biochemistry 18, 3506–3511.

    Article  PubMed  CAS  Google Scholar 

  60. Kim, J. H., Kim, S. H., Alfieri, A. A., and Young, C. W. (1984) Quercetin, an inhibitor of lactate transport and hyperthermic sensitizer of HeLa cells. Cancer Res. 44, 102–106.

    PubMed  CAS  Google Scholar 

  61. Song,C. W.,Lyons,J.C.,andLou,Y.(1993)Intra-andExtracellularpHinsolidtumors:Influenceontherapeutic response, in Drug Resistance in Oncology (Teicher, B. A., ed.), Marcel Dekker, New York, pp. 25–51.

    Google Scholar 

  62. Cook, J. A. and Fox, M. H. (1988) Effects of acute pH 6.6 and 42.0°C heating on the intracellular pH of Chinese hamster cells. Cancer Res. 48, 497–502.

    PubMed  CAS  Google Scholar 

  63. Park, H. J., Makepeace, C. M., Lyons, J. C., and Song, C. W. (1996) Effect of intracellular acidity and ionomycin on apoptosis in HL-60 cells. Eur. J. Cancer 32A, 540–546.

    Article  Google Scholar 

  64. Lee, H. S., Park, H. J., Lyons, J. C., Griffin, R. J., Auger, E. A., and Song, C. W. (1987) Radiation-induced apoptosis in different pH environment. Int. J. Radiat. Oncol. Biol. Phys. 38, 1079–1087.

    Article  Google Scholar 

  65. Lin, J.C, Levitt, S. H., and Song, C. W. (1991) Relationship between vascular thermotolerance and intratumor pH. Int. J. Radiat. Oncol. Biol. Phys. 22, 123–129.

    Article  Google Scholar 

  66. Ohtsubo, T., Wang, S., Takahashi, A., Ohnishi, K., Saito, H., Song, C. W., and Ohnishi, T. (1997) p53dependent induction of WAF 1 by low pH culture condition in human glioblastoma cells. Cancer Res. 57,3910–3913.

    PubMed  CAS  Google Scholar 

  67. Rottinger, E. M., Mendonca, M., and Gerweck, L. E. (1980) Modification of pH induced cellular inactivation by irradiation-Glial cells. Int. J. Radiat. Oncol. Biol. Phys. 6, 1659–1662.

    Google Scholar 

  68. Jahde, E., Glusenkamp, K. H., Klunder, I., Hulser, D. F., Tietze, L. F., and Rajewsky, M. F. (1989) Hydrogen ion-mediated enhancement of cytotoxicity of bis-chlorethylating drugs in rat mammary carcinoma cells in vitro. Cancer Res. 49, 2965–2972.

    PubMed  CAS  Google Scholar 

  69. Kennedy, K. A., McGurl, J. D., Leondaridis, L., and Alabaster, O. (1985) pH dependence of mitomycin C-induced cross-linking activity in EMT6 tumor cells. Cancer Res. 45, 3541–3547.

    Google Scholar 

  70. Gahr, A., Kain, A., Aalders, M., El-Gawly, H., and Smers, L. A. (1997) Cellular pharmacokinetics and cytotoxicity of camptothecin and topotecan at normal and acidic pH. Cancer Res. 57, 4811–4816.

    Google Scholar 

  71. Gerweck, L. E., Rhee, J. G., Koutcher, J. A., Song, C. W., and Urano, M. (1991) Regulation of pH in murine tumors and muscle. Radiat. Res. 126, 206–209.

    Article  PubMed  CAS  Google Scholar 

  72. Ward, K. A., DiPette, D. J., Held, T. N., and Jain, R. K. (1991) Effect of intravenous versus intraperitoneal glucose injection on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats. Cancer Res. 51, 3612–3616.

    Google Scholar 

  73. Vaupel, P. W. and Okunieff, P. G. (1988) Role of hypovolemic hemoconcentration in dose-dependent flow decline observed in murine tumors after intraperitoneal administration of glucose or mannitol. Cancer Res. 48, 7102–7106.

    PubMed  CAS  Google Scholar 

  74. Calderwood, S. K. and Dickson, J. A. (1980) Effect of hyperglycemia on blood flow, pH and response to hyperthermia (42°C) of the Yoshida sarcoma in the rat. Cancer Res. 40, 4728–4733.

    PubMed  CAS  Google Scholar 

  75. Leeper, D. B., Engin, K., Thistlethwaite, A. J., Hitchon, H. D., Cover, J. D., Li, D. J., and Tupchong, L. (1994) Human tumor extracellular pH as a function ofblood glucose concentration. lnt. J. Radiat. Oncol. Biol. Phys. 28, 935–943.

    Google Scholar 

  76. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845.

    Article  PubMed  CAS  Google Scholar 

  77. Kim, K. W., Bae, S. K., Lee, O. H., Bae, M. H., Lee, M. J., and Park, B. C. (1998) Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis ofhuman hepatocellular carcinoma. Cancer Res. 58, 348–351.

    PubMed  CAS  Google Scholar 

  78. Bar, R. S., Hoak, J. C., and Peacock, M. L. (1978) Insulin receptors in human endothelial cells: Identification and characterization. J. Cli. End. Met. 47, 699–702.

    Article  CAS  Google Scholar 

  79. Griffiths, L., Dachs, G. U., Bicknell, R., Harris, A. L., and Stratford, I. J. (1997) Influence of oxygen tension and pH on the expression ofplatelet-derived endothelial cells growth factor/thymidine phosphorylase in human breast tumor cells growth in vitro and in vivo. Cancer Res. 57, 570–572.

    PubMed  CAS  Google Scholar 

  80. Folkman, J. and Shing, Y. (1992) Angiogenesis. J. Biol. Chem. 267, 10,931–10,934.

    Google Scholar 

  81. Grass, J. D., Bradbury, J., Kay, R. R., and Peacy, M. J. (1983) Differentiation of cells is inhibited by agents that block the ATP-dependent protons pump (Na+/H+ ATPase) and stimulated by agent that increase intracellular pH. Nature 303, 244.

    Article  Google Scholar 

  82. Musgrove, E., Seaman, M., and Hedley, D. (1987) Relationship between cytoplasmic pH and proliferation during exponential growth and cellular quiescence. Experimental Cell Res. 172, 65–75.

    Article  CAS  Google Scholar 

  83. Taylor, I. W. and Hodson, P. J. (1984) Cell cycle regulation by environmental pH. J. Cellular Physiol. 121, 517–525.

    Article  CAS  Google Scholar 

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  1. Chang W. Song
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  2. HeonJoo Park
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  3. Brian D. Ross
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  1. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA

    Beverly A. Teicher

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Song, C.W., Park, H., Ross, B.D. (1999). Intra- and Extracellular pH in Solid Tumors. In: Teicher, B.A. (eds) Antiangiogenic Agents in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-453-5_4

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  • DOI: https://doi.org/10.1007/978-1-59259-453-5_4

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