Skip to main content
SpringerLink
Log in

Influence of Tumor pH on Therapeutic Response

  • Chapter
Cancer Drug Resistance

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

Abstract

The intratumor microenvironment is intrinsically acidic due mainly to accumulation of lactic acid as a result of increased aerobic and anaerobic glycolysis by the tumor cells. In general, the extracellular pH (pHe) in human tumors is below 7.0, whereas the intracellular pH (pHi) is maintained at neutral range, i.e.,>7.0, by powerful pHi control mechanisms. The low pHe and the significant gradients between pHe and pHi affect markedly the response of tumors to various treatments such as chemotherapy, radiotherapy and hyperthermia. For instance, the acidic pHe increases the cellular uptake of weakly acidic drugs such as cyclophosphamide and cisplatin and thus increases the effect of the drugs, whereas the acidic pHe retards the uptake of weakly basic drug such as doxorubicin and vinblastine, thereby reducing the effect of the drugs. The radiationinduced apoptosis is suppressed by an acidic environment, whereas the hyperthermiainduced cell death is potentiated by an acidic environment. Better understanding of the control mechanisms of pHe and pHi in tumors may lead to device effective treatment strategy of human tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Song CW, Lyon JC, Luo Y. Intra-and extracellular pH in solid tumors: influence on therapeutic response. In: Teicher BV, ed. Drug resistance in oncology. New York: Marcel Dekker, 1993:25–51.

    Google Scholar 

  2. Song CW, Park HJ, Ross BD. Intra-and extracellular pH in solid tumors. In Teicher BV, ed. Antiangiogenic adnets in cancer therapy. Totowa: Humana Press, 1998:51–64.

    Chapter  Google Scholar 

  3. Rhee JG, Kim TH, Levitt SH, Song CW. Changes in acidity of mouse tumors by hyperthermia. Int J Radiat Oncol Biol Phys 1985; 10:393–399.

    Google Scholar 

  4. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984; 2:343–366.

    Article  PubMed  CAS  Google Scholar 

  5. Webb SD, Sherratt JA, Fish RG. Mathematical modeling of tumour acidity: regulation of intracellular pH. J Theor Biol 1999; 196:237–250.

    Article  PubMed  CAS  Google Scholar 

  6. Gilles RJ, Raghunand N, Karczmar GS, et al. MRI of the tumor microenvironment. J Magn Reson Imaging 2002; 16:430–450.

    Article  Google Scholar 

  7. Svastove E, Hulikova A, Rafajova M, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 2004; 19:439–435.

    Article  CAS  Google Scholar 

  8. Aisenberg AC. The glycolysis and respiration of tumors. New York: Academic, 1961.

    Google Scholar 

  9. Kim GE, Lyons JC, Levitt SH, Song CW. Effects of amiloride onintracellularpH and thermosensitivity. Int J Radiat Oncol Biol Phys 1991; 20:541–549.

    PubMed  CAS  Google Scholar 

  10. Gerweck LE, Rhee JG, Koutcher JA, Song CW, Urano M. Regulation of pH in murine tumor and muscle. Radiat Res 1991; 126:206–209.

    Article  PubMed  CAS  Google Scholar 

  11. Lyons JC, Kim GE, Song CW. Modification of intracellular pH and thermosensitivity. Radiat Res 1992; 129:79–87.

    Article  PubMed  CAS  Google Scholar 

  12. Lyons JC, Ross B, Song CW. Enhancement of hyperthermia effect in vivo by amiloride and DIDS. Int J Radiat Oncol Biol Phys 1993; 25:95–103.

    PubMed  CAS  Google Scholar 

  13. Roos A, Baron WF. Intracellular pH. Physiol Rev 1981; 61:296–134.

    PubMed  CAS  Google Scholar 

  14. Song, CW. Effect of local hyperthermia in blood flow and microenvironment: a review. Cancer Res 1984; 44(Suppl):4721s–4730s.

    PubMed  CAS  Google Scholar 

  15. Vaupel P, Muller Klieser W, Otte J, Manz R, Kallinowski F. Blood flow, tissue oxygenation and pH distribution in malignant tumors upon localized hyperthermia. Strahlentherapie 1983; 159:73–81.

    PubMed  CAS  Google Scholar 

  16. Hetzel FW. Biological rationale for hyperthermia. Radiol Clin North Am 1987; 27:499–508.

    Google Scholar 

  17. Dewhirst MW, Gross JF, Sim D, Arnold P, Boyer D. The effect of rate of heating or cooling prior to heating on tumor and normal tissue microcirculatory blood flow. Biorheology 1984; 21:539–558.

    PubMed  CAS  Google Scholar 

  18. Jain RK, Ward-Hartely K. Tumor blood flow: characterization, modifications and role in hyperthermia. IEEE Trans Son Ultrason 1984; SU-31:504–526.

    Google Scholar 

  19. Song CW. Tumor blood flow response to heat. Funktionsanal Biol Syst 1991; 20:123–141.

    Google Scholar 

  20. Reinhold HS, Endrich B. Tumourmicrocirculation as a target for hyperthermia. Int J Hypertherm 1986; 2:111–137.

    CAS  Google Scholar 

  21. Jain RK. Determinant of tumor blood flow. A review. Cancer Res 1988; 48:2641–2658.

    PubMed  CAS  Google Scholar 

  22. Eddy HA. Microangiographic techniques in the study of normal and tumor tissue vascular systems. Microvasc Res 1976; 11:391–413.

    Article  PubMed  CAS  Google Scholar 

  23. Peterson HI. Tumor blood circulation: Angiogenesis, vascular morphology and blood flow of experimental and human tumors. Boca Raton: CRC Press, 1978.

    Google Scholar 

  24. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and possible implications for radiotherapy. Br J Cancer 1955; 9:539–549.

    PubMed  CAS  Google Scholar 

  25. Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res 1990; 50(Suppl):814s–819s.

    PubMed  CAS  Google Scholar 

  26. Hong SS, Lee H, Kim KW. HIF-1 a: a valid therapeutic target for tumor therapy. Cancer Res Treat 2004; 36:344–353.

    Article  Google Scholar 

  27. Mazure NM, Brahimi-Horn MC, Berta MA, et al. HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol 2004; 68:971–980.

    Article  PubMed  CAS  Google Scholar 

  28. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732.

    Article  PubMed  CAS  Google Scholar 

  29. Griffiths JR, McIntyre DJ, Howe FA, Stubbs M. Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid. Novartis Found Symp 2001; 240:46–62.

    Article  PubMed  CAS  Google Scholar 

  30. Busa WB, Nuccitelli R. Metabolic regulation via intracellular pH. Am J Physiol 1984; 246:R409–R438.

    PubMed  CAS  Google Scholar 

  31. Schornack PA, Gillies RJ. Contribution of cell metabolisms and H+ diffusion to the acidic pH of tumors. Neoplasia 2002; 5:135–145.

    Google Scholar 

  32. van der Berg AP. Tissue pH of human tumors and its variation upon therapy in tumor blood supply and metabolic microenvironment. Funktionsanal Biol Syst 1991; 20:234–235.

    Google Scholar 

  33. Hinke JA. Ction-selective microelectrodes for intracellular use. In: Eiserman G, ed. Glass electrodes for hydrogen and other cations. New York: Marcel Dekker, 1967:474–477.

    Google Scholar 

  34. Thomas RC. New design of a sodium-sensitive glass microelectrode. J Physiol 1970; 210:829–839.

    Google Scholar 

  35. Lin J-C, Levitt SH, Song CW. Relationship between vascular thermotolerance and intratumor pH. Int J Radiat Oncol Biol Phys 1991; 22:123–129.

    Google Scholar 

  36. Vaupel PW, Frinak S, Bicher HI. Heterogenous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 1981; 41:2008–2013.

    PubMed  CAS  Google Scholar 

  37. Ja’hde E, Rajewsky MF, Ba’umgart H. pH distribution in transplanted neural tumors and normal tissues of BDIX rats as measured with pH microelectrodes. Cancer Res 1982; 42:1498–1504.

    PubMed  CAS  Google Scholar 

  38. Meyer KA, Kammerling EM, Amtan L, et al. pH studies of malignant tissues in human being. 1948; 8:513–518.

    CAS  Google Scholar 

  39. Pampus F. Die Wasserstoffionenkonzentration des Hirngewebes bei raumfordernden intracraniellen Prozessen. Acta Neurochir 1963; 11:305–318.

    Article  CAS  Google Scholar 

  40. Ashby BS. pH studies in human malignant tumours. Lancet 1966; 2:312–315.

    Article  PubMed  CAS  Google Scholar 

  41. Thistlethwaite AJ, Leeper DB, Moylan DJ, et al. pH distribution in human tumors. Int J Radiat Oncol BiolPhys 1985; 11:1647–1652.

    CAS  Google Scholar 

  42. Wike-Hooley JL, van den Berg AP, van der Zee J, Reinhold HS. Human tumour pH and its variation. Eur J Cancer Clin Oncol 1985; 21:785–791.

    Article  PubMed  CAS  Google Scholar 

  43. van den Berg AP, Wike-Hooley JL, van den Berg-Blok AE, et al. Tumour pH in human mammary carcinoma. Eur J Cancer Clin Oncol 1982; 18:457–462.

    Article  PubMed  Google Scholar 

  44. Inch WR, Direct current potential and pH of several varieties of skin neoplasms. Can J Biochem Physiol 1954; 32:519–525.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  46. Naeslund J, Senson KE. Investigations on the pH of malignant tumors in mice and humans after the administration of glucose. Acta Obstet Gynecol Scand 1953; 32:359–367.

    PubMed  CAS  Google Scholar 

  47. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumours: a review. Cancer Res 1989; 49:6449–6465.

    PubMed  CAS  Google Scholar 

  48. Griffiths JR. Are cancer cells acidic? Br J Cancer 1991; 64:425–427.

    PubMed  CAS  Google Scholar 

  49. Engin K, Leeper DB, Cater JR, et al. Extracellular pH distribution in human tumours. Int J Hyperthermia 1995; 11:211–216.

    PubMed  CAS  Google Scholar 

  50. Eden M, Haines B, Kahler H. The pH of rat tumors measured in vivo. J Natl Cancer Inst 1955; 16:541–556.

    PubMed  CAS  Google Scholar 

  51. Evanochko WT, Ng TC, Lilly, MB, et al. In vivo 31P-NMR study of the metabolism of murine mammary 16/C adenocarcinoma and its response to chemotherapy, x-irradiation and hyperthermia. Proc Natl Acad Sci U S A 1983; 80:334–338.

    Article  PubMed  CAS  Google Scholar 

  52. Gillies RJ, Ogina T, Shulman RG, Ward DC. 31P nuclear magnetic resonance evidence for the regulation of intracellular pH by Ehrlich ascites tumor cells. J Cell Biol 1982; 95:24–28.

    Article  PubMed  CAS  Google Scholar 

  53. Evelhoch JL, Sapareto SA, Jick DEL, Ackerman JJH. In vivo metabolic effects of hyperglycemia in murine radiation induced fibrosarcoma: a 31P-NMR investigation. Proc Natl Acad Sci USA 1984; 81:6496–6500.

    Article  PubMed  CAS  Google Scholar 

  54. Okuneiff PG, Koutcher JA, Gerweck L, et al. Tumor size dependent metabolic changes in a murine fibrosarcoma: use of Fourier transformed 31P-NMR to evaluate energy metabolism. Int J Radiat Oncol BiolPhys 1986; 12:793–799.

    Article  Google Scholar 

  55. Madshus IH. Regulation of intracellular pH in eukaryotic cells. J Biochem 1988; 250:1–8.

    CAS  Google Scholar 

  56. Grinstien S, Rothstein S. Mechanisms of regulation of the Na+/H+exchanger. J Membrane Biol 1986; 90:1–12.

    Article  Google Scholar 

  57. Frelin C, Vigne P, Ladoux A, Lazdunski M. The regulation of the intracellular pH in cells from vertebrates. Eur J Biochem 1988; 174: 3–14.

    Article  PubMed  CAS  Google Scholar 

  58. Tannock, IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989; 49:4373–4384.

    PubMed  CAS  Google Scholar 

  59. Aronson PS. Kinetic properties of the plasma membrane Na+/H+ exchange. Annu Rev Physiol 1985; 47:545–560.

    Article  PubMed  CAS  Google Scholar 

  60. Cassel D, Katz M, Rotman M. 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 B iol Chem 1986; 261:5460–5466.

    CAS  Google Scholar 

  61. Zhung YX, Cragoe EJ Jr, Glaser L, Cassel D. Characterization of potent Na+/H+exchange inhibitor from the aniloride series in A431 cells. Biochemistry 1984; 23:4481–4488.

    Article  Google Scholar 

  62. Cassel D, Scharf O, Rotman M, et al. Characterization of Na+-linked and Na+-independent C1-/HCO3-exchange systems in Chinese hamster lung fibroblasts. J Biol Chem 1988; 263:6122–6127.

    PubMed  CAS  Google Scholar 

  63. Boron WF. Intracellular pH regulation in epithelial cells. Am Rev Physiol 1986; 43:377–388.

    Article  Google Scholar 

  64. Jentsch TJ, Matthes H, Keller SK, Wiederholt M. Carrier-mediated reabsorption of small peptides in renal proximal tribute. Am J Physiol 1986; 251:F945–F968.

    Google Scholar 

  65. Grassl SM, Aronson PS. Na+/CHO3- Co-transport in basolateral membrane vesicles isolated from rabbit renal cortex. J Biol Chem 1986; 26:8778–8783.

    Google Scholar 

  66. Hutton JC. The internal pH and membrane potential of the insulin-secretory granule. J Biochem 1982; 204:171–178.

    CAS  Google Scholar 

  67. Thomas RC. Ionic mechanism of the H+ pump in a snail neurone. Nature 1976; 262: 54–55.

    Article  PubMed  CAS  Google Scholar 

  68. Russell JM, Boron WF. Role of chloride transport in regulation of intracellular pH. Nature 1976; 264:73–74.

    Article  PubMed  CAS  Google Scholar 

  69. Boron WF, Hogan E., Russell JM. pH-sensitive activation of the intracellular-pH regulation system in squid axons by ATP-ψ-S. Nature 1988: 332:2672–265.

    Article  Google Scholar 

  70. Moolenaar WH, Tertoolen LGL, de Laat SW. The regulation of cytoplasmic pH in human fibroblasts. J Biol Chem 1984; 259:7563–7569.

    PubMed  CAS  Google Scholar 

  71. Belt J A, Thomas JA, Buchsbaum RN, Racker E. Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavanoids. Biochemistry 1979; 18:3506–3511.

    Article  PubMed  CAS  Google Scholar 

  72. Kim JH, Kim SH, Aldieri AA, Young CW. Quercetin, an inhibitor of lactate transport and hyperthermic sensitizer of HeLa cells. Cancer Res 1984; 44:102–106.

    PubMed  CAS  Google Scholar 

  73. Turpaev KT. Reactive oxygen species and regulation of gene expression. Biochemistry (Mosc) 2002; 67:281–292.

    Article  CAS  Google Scholar 

  74. Subarsky P, Hill RP. The hypoxic tumour microencironment and metastatic progression. Clin Exp Metastasis 2003; 20:237–250.

    Article  PubMed  CAS  Google Scholar 

  75. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev 2004; 23:293–310.

    Article  PubMed  CAS  Google Scholar 

  76. Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol 2001; 28:29–35.

    Article  PubMed  CAS  Google Scholar 

  77. Ohtsubo T, Wang X, Takahashi A, et al. p53-dependent induction of WAF1 by low pH culture condition in human glioblastoma cells. Cancer Res 1997; 57:3910–3913.

    PubMed  CAS  Google Scholar 

  78. Griffiths L, Dachs GU, Bicknell R, et al. Influence of oxygen tension and pH on the expression of platelet-derived endothelial cells growth factor/thymidine phosphorylase in human breast tumor cells growth in vitro and in vitro. Cancer Res 1997; 57:570–572.

    PubMed  CAS  Google Scholar 

  79. Schlappack OK, Zimmermann A, Hill RP. Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Br J Cancer 1991; 64:663–670.

    PubMed  CAS  Google Scholar 

  80. Jang A, Hill RP. An examination of the effects of hypoxia, acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. Clin Exp Metastasis 1997; 15:469–483

    Article  PubMed  CAS  Google Scholar 

  81. Hill RP, Jaeger KD. Jang A, Cairns R. pH, hypoxia and metastasis. The tumor microenvironment: causes and consequences of hypoxia and acidity. Chichester: Wiley, 2001:154–168.

    Chapter  Google Scholar 

  82. Kalliomaki T, Hill RP. Effects of tumour acidification with glucose+MIBG on the spontaneous metastatic potential of two murine cell lines. Br J Cancer 2004: 90:1842–1849

    PubMed  CAS  Google Scholar 

  83. Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol 2000; 76:589–605.

    Article  PubMed  CAS  Google Scholar 

  84. Park HJ, Lyons JC, Griffin RJ, Lim BU, Song CW. Apoptosis and cell cycle progression in an acidic environment after irradiation. Radiat Res 2000; 153:295–304.

    Article  PubMed  CAS  Google Scholar 

  85. Rotin D, Wan P, Grinstien S, Tannock I. Cytotoxicity of compounds that interfere with the regulation of intracellular pH: a potential new class of anticancer drugs. Cancer Res 1987; 47:1497–1505.

    PubMed  CAS  Google Scholar 

  86. Park HJ, Makepeace CM, Lyons JC, Song CW. Effect of intracellular acidity and ionomycin on apoptosis in HL-60 cells. Eur J Cancer 1996; 32A:540–546.

    Article  PubMed  CAS  Google Scholar 

  87. Park HJ, Lyons JC, Ohtsubo T, Song CW. Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 1999; 80:1892–1897.

    Article  PubMed  CAS  Google Scholar 

  88. Newell KT, Tannock I. Reduction of intracellular pH as a possible mechanism for killing cells in acidic regions of solid tumors: effect of carbonylcyanide03-chrophgenylhydrazone. Cancer Res 1989; 49:4477–4482.

    PubMed  CAS  Google Scholar 

  89. Haveman J. The pH of the cytoplasm as an important factor in the survival of vitro cultured malignant cells after hyperthermia. Effects of carbonylcyanide-3-chlorophenylhyrazone. Eur J Cancer 1979; 15:1281–1288.

    PubMed  CAS  Google Scholar 

  90. Miyakoshi J, Oda W, Harata M, et al. Effects of amiloride on thermosensitivity of Chinese hamster cells under neutral and acidic pH. Cancer Res 1986; 46:1840–1843.

    PubMed  CAS  Google Scholar 

  91. Ruifrok ACC, Konings AWTR. Effects of amiloride on hyperthermic cell killing of normal and thermotolerant mouse fibroblast LM cells. Int J Radiat Biol 1987; 52:385–392.

    Article  CAS  Google Scholar 

  92. Varnes Me, Glazver KG, Gray C.pH-dependent effects of the ionophore nigericin on response of mammalian cells to radiation and heat treatment. Radiat Res 1989; 117:285–292.

    Article  Google Scholar 

  93. Song CW, Lyons JC, Griffin RJ, et al. Increase in thermosensitivity of tumor cells by lowering intracellular pH. Cancer Res 1993; 53:1599–1601.

    PubMed  CAS  Google Scholar 

  94. Song CW, Lyons JC, Griffin RJ, Makepeace CM. Thermosensitization by lowering intracellular pH with EIPA. Radiother Oncol 1993; 27:252–258.

    Article  PubMed  CAS  Google Scholar 

  95. Song CW, Lyons JC, Makepeace CM, et al. Effects of HMA, an analog of amiloride, on the thermosensitivity of tumors in vivo. Int J Radiat Oncol Biol Phys 1994; 30:133–139.

    PubMed  CAS  Google Scholar 

  96. Song CW, Kim GE, Lyons JC, et al. Thermosensitization by increasing intracellular acidity with amiloride and its analogs. Int. J Radiat Oncol Biol Phys 1994; 30:1161–1169.

    PubMed  CAS  Google Scholar 

  97. Takasu T, Lyons JC, Park HJ, Song CW. Apoptosis and perturbation of cell cycle progression by hyperthermia in an acidic environment. Cancer Res 1998; 58:2504–2508.

    PubMed  CAS  Google Scholar 

  98. Hirpara JL, Clements MV, Pervaiz A. Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. J Biol Chem 2001; 276:514–521.

    Article  PubMed  CAS  Google Scholar 

  99. Ahmad KS, Iskandar KB, Hirpara JL, et al. Hydrogen peroxide-mediated cytosolic acidification is a signal for mitochondrial translocation of Bax during drug-induced apoptosis of tumor cells. Cancer Res 2004; 64:7867–7878.

    Article  PubMed  CAS  Google Scholar 

  100. Lee H-S, Park HJ, Lyons JC, et al. Radiation-induced apoptosis in different pH environments in vitro. Int J Radiat Oncol Biol Phys 1997; 38:1079–1087.

    Article  PubMed  CAS  Google Scholar 

  101. Park HJ, Lyons JC, Ohtsubo T, Song CW. Cell cycle progression and apoptosis after irradiation in an acidic environment. Cell Death Differ 2000; 7:729–738.

    Article  PubMed  CAS  Google Scholar 

  102. Ohtsubo T, Igawa H, Saito T, et al. Acidic environment modifies heat-or radiation-induced apoptosis in human maxillary cancer cells. Int J Radiation Oncology Biol Phys 2001; 49:1391–1399.

    Article  CAS  Google Scholar 

  103. Park HJ, Lee SH, Chung H, et al. Influence of environmental pH on G2-phase arrest caused by ionizing radiation. Radiat Res 2003; 159:86–93.

    Article  PubMed  CAS  Google Scholar 

  104. Freeman ML, Sierra E. An acidic extracellular environment reduces the fixation of DNA damage. Radiat Res 1984; 97:154–161.

    Article  PubMed  CAS  Google Scholar 

  105. Holahan EV. Stuart PK, Dewey WC. Enhancement of survival of CHO cells by acidic pH after X-irradiation. Radiat Res 1982; 89:433–435.

    Article  PubMed  CAS  Google Scholar 

  106. Haveman J. The influence of pH on the survival after X-irradiation of cultured malignant cells. Effects of carbonylbyanide 3-chlorophenylhydrazone. Int J Radiat Biol 1980; 37:201–205.

    Article  CAS  Google Scholar 

  107. Choi EK, Robert K, Gfiffin RJ, et al. Effect of pH on radiation-induced p53 expression. Int J Radiat Oncol Biol Phys 2004; 60:1264–1271.

    Article  PubMed  CAS  Google Scholar 

  108. Freeman ML, Dewey WC, Hopewood LE. Effect of pH on hyperthermic cell killing: brief communication. J Natl Cancer Inst 1977; 58:1837–1839.

    PubMed  CAS  Google Scholar 

  109. Gerweck LE. Modification of cell lethality at elevated temperatures. Radiat Res 1977; 70:224–235.

    Article  PubMed  CAS  Google Scholar 

  110. Gerweck LE, Dahlberg WK, Greco B. Effect of pH on single or fractionated heat treatment at42-5°C. Cancer Res 1983; 43:1163–1167.

    PubMed  CAS  Google Scholar 

  111. Nlsen OS, Overgaard J. Effect of extracellular pH on thermotolerance and recovery of hyperthermia damage in vitro. Cancer Res 1979; 39:2772–2778.

    Google Scholar 

  112. Goldin EM, Leeper DB. The effect of reduced pH on the induction of thermotolerance. Radiology 1981: 141:505–508.

    PubMed  CAS  Google Scholar 

  113. KG Hofer, Mivichi NF. Tumor cell sensitivity to hyperthermia as a function of extracellular and intracellular pH. J Natl Cancer Inst 1980; 65:621–625.

    PubMed  CAS  Google Scholar 

  114. Chu GL, Dewey WC. The role of low intracellular or extracellular pH in sensitization of hyperthermia. Radiat Res 1988; 11:4154–4167.

    Google Scholar 

  115. Hahn GM, Shiu E. Adaptation of low pH modified thermal and thermochemical response of mammalian cells. Int J Hypertherm 1986; 2:379–387.

    CAS  Google Scholar 

  116. Cook JA, Fox MH. Effects of acute pH 6.6 and 42.0°C heating on the intracellular pH of Chinese hamster cells. Cancer Res 1988; 48:497–502.

    PubMed  CAS  Google Scholar 

  117. van den Berg A, Wike-Hooley JL, Broekmayer-Reurink MP, van der Zee J, Reinhold HS. The relationship between the unmodified initial tissue pH of human tumors and the response to combined radiotherapy and local hyperthermia treatment. Eur J Cancer Clin Oncol 1989; 25:73–78.

    Article  PubMed  Google Scholar 

  118. Hetzel FW, Avery K, Chopp M. Hyperthermic &quote;dose&quote; dependent changes in intralesional pH. Int J Radiat Oncol Biol Phys 1989; 16:183–186.

    PubMed  CAS  Google Scholar 

  119. Kang, MS, Song CW, Levitt, SH. The role of vascular function in the response of tumors in vivo to hyperthermia. Cancer Res 1980; 40:1130–1135.

    PubMed  CAS  Google Scholar 

  120. Thistlethwaite AJ, Leeper DB, Moylan DJ, Nerlinger RE. pH distribution in human tumors. Int J Radiat Oncol Biol Phys 1985; 11:1647–1652.

    PubMed  CAS  Google Scholar 

  121. Canter RJ, Zhou R, Kesmodel SB, et al. Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma. Ann Surg Oncol 2004; 11:265–273.

    Article  PubMed  Google Scholar 

  122. Mahoney BP, Raghunand N, Baggett B, et al. Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemo therapeutic agents in vitro. Biochem Pharmacol 2003; 66:1207–1218.

    Article  PubMed  CAS  Google Scholar 

  123. Raghunand N, Mahoney BP, Gilles RJ. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol 2003; 66:1219–1229.

    Article  PubMed  CAS  Google Scholar 

  124. Jahde E, Glusenkamp KH, Klunder I, Hulser DF, Tietze LF, Rajewsky MF. Hydrogen ion-mediated enhancement of cytotoxicity of bis-chlorethylating drugs in rat mammary carcinoma cells in vitro. Cancer Res 1989; 49:2965–2972.

    PubMed  CAS  Google Scholar 

  125. Jahde E, Glusenkamp KH, Rajewsky MF. Nigericin enhances mafosfamide cytotoxicity at a low extracellular pH. Cancer Chemother Pharmcol 1991; 27:440–444.

    Article  CAS  Google Scholar 

  126. Skarsgard LD, Chaplin DJ, Wilson DJ, et al. The effect of hypoxia and low pH on the cytotoxicity of melphalan and chlorambucil in vitro (abstract 23). Proceedings of the 7th International Conference on Chemical Modifiers of Cancer Treatment, Clearwarter, Florida, 2-5 Feb 1992.

    Google Scholar 

  127. Kwok TT, Twentyman PR. Effects of changes in oxygen tension, pH and glucose concentration on the response to CCNU and EMT6 mouse tumor monolayer cells and multicellular spheroids. Int J Radiat Oncol Biol Phys 1988; 14:1221–1229.

    PubMed  CAS  Google Scholar 

  128. Euler J, Sauerman G, Priesching A. Wirkung von temperature, pH und thiotepa auf angehraten und thymodineinbau von aszitestumorzellen. Wien Klin Wocheschr 1974; 86:211–219.

    CAS  Google Scholar 

  129. Connors TA, Mitchley BCV, Rosenoer VM, Ross WCJ. The effect of glucose pretreatment on the cardinostatic and toxic activities of some alkylating agents. Biochem Pharm 1964; 13:395–400.

    Article  PubMed  CAS  Google Scholar 

  130. Oskinsky S, Bubnovskyja L, Sergienko T. Tumor pH under induced hyperglycemia and efficacy of chemotherapy. Anticancer Res 1987; 7:199–202.

    Google Scholar 

  131. Hahn GM, Shiu EC. Effect of pH and elevated temperatures on cytotoxicity of some chemotherapeutic agents on Chinese hamster cells in vitro. Cancer Res 1983; 43:5789–5791.

    PubMed  CAS  Google Scholar 

  132. Ojugo AS, McSheehy PM, Stubbs M, et al. Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells. Br J Cancer 1998; 77:873–879.

    PubMed  CAS  Google Scholar 

  133. Kennedy KA, McGurl JD, Leondaridis L, Alabaster O. pH dependent of mitomycin C-induced cross linking activity in MET6 tumor cells. Cancer Res 1985; 45:3541–3547.

    PubMed  CAS  Google Scholar 

  134. Urano M, Kahn J, Kenton LA. Effect of bleomycin on murine tumor cells at elevated temperatures and two different pH values. Cancer Res 1988; 48:616–619.

    Google Scholar 

  135. Born R, Eicholtz-Wirth H. Effect of different physiological conditions on the action of Adriamycin on Chinese hamster cells in vitro. Br J Cancer 1981; 44:241–246.

    PubMed  CAS  Google Scholar 

  136. Hindenberg AA, Stewart VJ, Baker MA, Taub RN. Effect of pH on cellular accumulation of duanorubicvin. Am Assoc Cancer Res 1987; 28:261 (abstract no. 1031).

    Google Scholar 

  137. Ferguson PJ, Phillips JR, Selner M, Case CE. Differential activity of vincristine and vinblastine against cultured cells. Cancer Res 1984; 44:3307–3312.

    PubMed  CAS  Google Scholar 

  138. Vukovic, V, Tannock IF. Influence of low pH on cytotoxicity of paclitaxelmitoxantrone and topotecan. Br J Cancer 1997; 75:1167–1172.

    PubMed  CAS  Google Scholar 

  139. Hahn GM. Hyperthermia to enhance drug delivery. In: Rational basis for chemotherapy. New York: Alan R. Liss, 1983:427–436.

    Google Scholar 

  140. Herman TS, Teicher BA, Collins LS. Effect of hypoxia and acidosis on the cytotoxicity of four platinum complexes at normal and hyperthermic temperatures. Cancer Res 1988; 48:2342–2347.

    PubMed  CAS  Google Scholar 

  141. Teicher BA, Herman TS, Pfeffer MR, et al. Interaction of PtCl4(Fast Black)2 with hyperthermia. Cancer Res 1989; 49:6208–6219.

    PubMed  CAS  Google Scholar 

  142. Ward JH, DipPette DJ, Held TN, Jain RK. Effect of intravenous versus intraperitoneal glucose injection on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats. Cancer Res 1991; 51:3612–3616.

    PubMed  CAS  Google Scholar 

  143. Vaupel PW, Okunieff PG. Role of hypovolemic hemoconcentration in dose-dependent flow decline observed in murine tumors after interperitoneal administration of glucose or mannitol. Cancer Res 1988; 48:7102–7106.

    PubMed  CAS  Google Scholar 

  144. Calderwood SK, Dickson JA. Effect of hyperglycemia on blood flow, pH and response to hyperthermia (42°C) of the Yoshida sarcoma in the rat. Cancer Res 1980; 40:4728–4733.

    PubMed  CAS  Google Scholar 

  145. Voorhees WD, Babbs CF. Hydralazine-enhanced selective heating of transmissible venereal tumor implanted in dogs. Eur J Cancer Clin Oncol 1982; 19:1027–1033.

    Article  Google Scholar 

  146. Lin J-C, Song CW. Effects of hydralazine on the blood flow in RIF-1 tumors and normal tissues of mice. Radiat Res 1990; 124:171–177.

    Article  PubMed  CAS  Google Scholar 

  147. Hasegawa T, Song CW. Effect of hydralazine on the blood flow in tumors and normal tissues of rats. Int J Radiat Oncol Biol Phys 1991; 20:1001–1007.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Therapeutic Radiology/Radiation Oncology, University of Minnesota Medical School, Minneapolis, MN

    Chang W. Song PhD & Robert Griffin PhD

  2. Department of Therapeutic Radiology/Radiation Oncology, University of Minnesota Medical School, Minneapolis, MN

    Heon Joo Park md, PhD

  3. Department of Microbiology, Medical School, Inha University, Inchon, Korea

    Heon Joo Park md, PhD

Authors
  1. Chang W. Song PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Griffin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heon Joo Park md, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Song, C.W., Griffin, R., Park, H.J. (2006). Influence of Tumor pH on Therapeutic Response. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-035-5_2

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-530-9

  • Online ISBN: 978-1-59745-035-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation