Pathophysiological and vascular characteristics of tumours and their importance for hyperthermia: Heterogeneity is the key issue

International Journal of Hyperthermia

Volumn 26, Issue 3, 2010, Pages 211-223

  Vaupel, Peter W ^a   Kelleher, Debra K ^b  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^b UNIVERSITY MEDICAL CENTER MAINZ   (Germany)

Author keywords

Hyperthermia; Tumour bioenergetics; Tumour blood flow; Tumour oxygenation; Tumour pH

Indexed keywords

ANGIOGENESIS; BLOOD FLOW; BLOOD FLOW VELOCITY; CELL HYPOXIA; CELL PH; ENERGY RESOURCE; HIGH TEMPERATURE; HUMAN; HYPERTHERMIC THERAPY; INTUSSUSCEPTION; MICROCIRCULATION; NEOPLASM; NONHUMAN; OXYGEN CONSUMPTION; OXYGEN TENSION; OXYGENATION; PATHOPHYSIOLOGY; REVIEW; TEMPERATURE DEPENDENCE; TUMOR BLOOD FLOW; TUMOR VASCULARIZATION; VASCULARIZATION;

FEVER; HEMORHEOLOGY; HUMANS; MICROCIRCULATION; NEOPLASMS; OXYGEN CONSUMPTION;

EID: 77951133615     PISSN: 02656736     EISSN: 14645157     Source Type: Journal    
DOI: 10.3109/02656731003596259     Document Type: Review

References (131)

1. Vaupel P. Physiological mechanisms of treatment resistance. In: Molls M, Vaupel P, Nieder C, Anscher MS, editors. The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies. Berlin, Heidelberg, New York: Springer; 2009. pp 273-290.
2. Horsman MR, Overgaard J. Hyperthermia: A potent enhancer of radiotherapy. Clin Oncol 2007;19:418-426.
3. Vaupel P. Pathophysiology of solid tumors. In: Molls M, Vaupel P, Nieder C, Anscher MS, editors. The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies. Berlin, Heidelberg, New York: Springer; 2009. pp 51-92.
4. Vaupel P. Pathophysiological mechanisms of hyperthermia in cancer therapy. In: Gautherie M, editor. Biological Basis of Oncologic Thermotherapy. Berlin, Heidelberg, New York: Springer; 1990. pp 73-134.
5. Vaupel P, Kelleher DK. Metabolic status and reaction to heat of normal and tumor tissue. In: Seegenschmiedt MH, Fessenden P, Vernon CC, editors. Thermoradiotherapy and Thermochemotherapy. Vol.1. Berlin, Heidelberg, New York: Springer; 1995. pp 157-176.
6. Vaupel P, Kallinowski F. Physiological effects of hyperthermia. Rec Res Cancer Res 1987;104:71-109.
7. Vaupel P, Kallinowski F, Kluge M. Pathophysiology of tumors in hyperthermia. Rec Res Cancer Res 1988;107:65-75.
8. Gerweck LE. Modifiers of thermal effects: Environmental factors. In: Urano M, Douple E, editors. Hyperthermia and Oncology. Vol.1. Utrecht: VSP; 1988. pp 83-98.
9. Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, Sanders LL, Dewhirst MW. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 2005;23:3079-3085.
10. Thrall DE, Larue SM, Pruitt AF, Case B, Dewhirst MW. Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas. Int J Hyperthermia 2006;22:365-373.
11. Sutherland RM. Cell and environment interactions in tumor microregions: The multicell spheroid model. Science 1988; 240:177-184.
12. Bussink J. The Tumor Microenvironment and Effects of Hypoxia Modification. Nijmegen: Proefschrift, Katholieke Universiteit; 2000.
13. Goode JA, Chadwick DJ, editors, The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity. Novartis Foundation Symposium 240, Chichester, New York: John Wiley; 2001.
14. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 1989;49:6449-6465.
15. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Sem Radiat Oncol 2004;14:198-206.
16. Vaupel P. Blood flow and metabolic microenvironment of brain tumors. J Neuro-Oncol 1994;22:261-267.
17. Vaupel P, Kelleher DK, editors, Tumor Hypoxia. Stuttgart: Wissenschaftliche Verlagsges; 1999.
18. Vaupel P, Jain RK, editors, Tumor Blood Supply and Metabolic Microenvironment. Characterization and Implications for Therapy. Stuttgart: Fischer; 1991.
19. Vaupel P, Höckel M. Blood supply, oxygenation status and metabolic micromilieu of breast cancers: Characterization and therapeutic relevance. Int J Oncol 2000;17:869-879.
20. Molls M, Vaupel P, editors, Blood Perfusion and Microenvironment of Human Tumors. Berlin, Heidelberg, New York: Springer; 2000.
21. Vaupel PW. Blood Flow, Oxygenation, Tissue pH Distribution, and Bioenergetic Status of Tumors. Lecture
22. Berlin: Ernst Schering Research Foundation; 1994.
23. Vaupel P. Physiological properties of malignant tumours. NMR Biomed 1992;5:220-225.
24. Barnikol WKR. Temperatur, pH-Wert, Säurebelastung und Filtrierbarkeit normaler menschlicher Erythrozyten: In-vitro- Untersuchungen. Mögliche Bedeutung für die hypertherme hyperazidotische Tumortherapie [Temperature, pH value, acid load and filtrability of normal human erythrocytes: In vitro studies. Possible significance for hyperthermic hyperacidotic tumor therapy]. Arch Geschwulstforsch 1989;59:11-17.
25. Kavanagh BD, Coffey BE, Needham D, Hochmuth RM, Dewhirst MW. The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer 1993;67:734-741.
26. Fajardo LF, Prionas SD. Endothelial cells and hyperthermia. Int J Hyperthermia 1994;10:347-353.
27. Fajardo LF, Prionas SD, Kowalski J, Kwan HH. Hyperthermia inhibits angiogenesis. Radiat Res 1988;114: 297-306.
28. Sawaji Y, Sato T, Takeuchi A, Hirata M, Ito A. Antiangiogenic action of hyperthermia by suppressing gene expression and production of tumour-derived vascular endothelial growth factor in vivo and in vitro. Br J Cancer 2002;86:1597-1603.
29. Roca C, Primo L, Valdembri D, Cividalli A, Declerck P, Carmeliet P, Gabriele P, Bussolino F. Hyperthermia inhibits angiogenesis by a plasminogen activator inhibitor 1-dependent mechanism. Cancer Res 2003;63:1500-1507.
30. Bicher HI, Sandhu TS, Vaupel P, Hetzel FW. Effect of localized microwave hyperthermia on physiological responses. J Natl Cancer Inst 1980;61:217-219.
31. Eddy HA. Alterations in tumor microvasculature during hyperthermia. Radiology 1980;137:515-521.
32. Emami B, Nussbaum GH, Ten Haken RK, Hughes WL. Physiological effects of hyperthermia: Response of capillary blood flow and structure to local tumor heating. Radiology 1980;137:805-809.
33. Emami B, Song CW. Physiological mechanisms in hyperthermia: A review. Int J Radiat Oncol Biol Phys 1984;10:289-295.
34. Reinhold HS, Endrich B. Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia 1986;2:111-137.
35. Reinhold HS, Van den Berg-Blok AP. Effects of hyperthermia on blood flow and metabolism. In: Field SB, Hand JW, editors. An Introduction to the Practical Aspects of Clinical Hyperthermia. London, New York: Taylor & Francis; 1990. pp 77-107.
36. Reinhold HS. Physiological effects of hyperthermia. Rec Res Cancer Res 1988;107:32-43.
37. Song CW. Physiological factors in hyperthermia. J Natl Cancer Inst 1980;61:169-176.
38. Song CW. Effect of local hyperthermia on blood flow and microenvironment. Cancer Res 1984;44:S4721-S4730.
39. Song CW, Park H, Griffin RJ. Improvement of tumor oxygenation by mild hyperthermia. Radiat Res 2001;155: 512-528.
40. Song CW, Choi IB, Nah BS, Sahu SK, Osborn JL. Microvasculature and perfusion in normal tissues and tumors. In: Seegenschmiedt MH, Fessenden P, Vernon CC, editors. Medical Radiology-Diagnostic Imaging and Radiation Oncology. Heidelberg: Springer; 1995. pp 139-156.
41. Vaupel P, Frinak S, Mueller-Klieser W, Bicher HI. Impact of localized hyperthermia on the cellular microenvironment in solid tumors. Natl Cancer Inst Monogr 1982;61:207-209.
42. Endrich B, Hammersen F, Messmer K. Hyperthermiainduced changes in tumor microcirculation. Rec Res Cancer Res 1988;107:44-59.
43. Endrich B. Hyperthermie und Tumormikrozirkulation. Eine kritische Wertung experimenteller und klinischer Befunde [Hyperthermia and tumor microcirculation. A critical evaluation of experimental and clinical data.]. Beitrg Onkol 1988;31:1-138.
44. Dudar TE, Jain RK. Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res 1984;44:605-612.
45. Vujaskovic Z, Song CW. Physiological mechanisms underlying heat-induced radiosensitization. Int J Hyperthermia 2004;20:163-174.
46. Thews G, Vaupel P. Vegetative Physiologie. Vol.5. Auflage. Heidelberg: Springer; 2005.
47. Kelleher DK, Engel T, Vaupel P. Changes in microregional perfusion, oxygenation, ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A hyperthermia. Int J Hyperthermia 1995;11:241-255.
48. Vaupel P, Kelleher DK, Thews O. Microtopology of local perfusion, oxygenation, metabolic and energetic status, and interstitial pH in malignant tumors: techniques and characterization. Exptl Oncol 2000;22:15-25.
49. Jones EL Prosnitz LR, Dewhirst MW, Marcom PK, Hardenbergh PH, Marks LB, Brizel DM, Vujaskovic Z. Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer. Clin Cancer Res 2004;10:4287-4293. (Pubitemid 38878865)
50. Shakil A, Osborn JL, Song CW. Changes in oxygenation status and blood flow in a rat tumor model by mild hyperthermia. Int J Radiat Oncol Biol Phys 1999;43:859-865.
51. Song CW, Park HJ, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia 2005;21:761-767.
52. Griffin RJ, Dings RPM, Jamshidi-Parsian A, Song CW. Mild temperature hyperthermia and radiation therapy: role of tumor vascular thermotolerance and relevant physiological factors. Int J Hyperthermia 2010, in press.
53. Gerner EW, Schneider MJ. Induced thermal resistance in HeLa cells. Nature 1975;256:500-502.
54. Henle KJ, Kramuz JE, Leeper DB. Induction of thermotolerance in Chinese hamster ovary cells by high (45°) or low (40°) hyperthermia. Cancer Res 1978;38:570-574.
55. Vujaskovic Z, Poulson JM, Gaskin AA, Thrall DE, Page RL, Charles HC, MacFall JR, Brizel DM, Meyer RE, Prescott DM, et al. Temperature-dependent changes in physiological parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment. Int J Radiat Oncol Biol Phys 2000;46: 179-185.
56. Viglianti BL, Lora-Michiels M, Poulson JM, Lan L, Yu D, Sanders L, Craciunescu O, Vujaskovic Z, Thrall DE, MacFall J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy. Clin Cancer Res 2009;15:4993-5001.
57. Vaupel, PW. Effects of physiological parameters on tissue response to hyperthermia: New experimental facts and their relevance to clinical problems. In: Gerner EW, Cetas TC, editors. Hyperthermic Oncology 1992. Tucson: Arizona Board of Regents; 1993. pp 17-23.
58. Waterman FM, Fazekas J, Nerlinger RE, Leeper DB. Blood flow rates in human tumors during hyperthermia treatments as indicated by thermal washout. Radiat Res 1982;91:426-427.
59. Waterman FM, Nerlinger RE, Moylan III DJ, Leeper DB. Response of human tumor blood flow to local hyperthermia. Int J Radiat Oncol Biol Phys 1987;13:75-82.
60. Groebe K, Kallinowski F, Vaupel P. Is the division of heated tissue into temperature equivalent zones suitable for estimation of tumor blood flow from thermal clearance curves? Int J Radiat Oncol Biol Phys 1987;13:917-920.
61. Waterman FM, Tupchong L, Nerlinger R, Matthews J. Blood flow in human tumors during local hyperthermia. Int J Radiat Oncol Biol Phys 1991;20:1255-1262.
62. Waterman FM, Tupchong L, Matthews J, Nerlinger R. Mechanisms of heat removal during local hyperthermia. Int J Radiat Oncol Biol Phys 1989;17:1049-1055.
63. Lammertsma AA, Wilson CB, Jones T. In vivo physiological studies in human tumors using positron emission tomography. Funktionsanalyse biolog Systeme 1991;20:319-325.
64. Bowman HF, Martin GT, Newman WH, Kumar S, Welch C, Bornstein B, Herman TS. Human tumor perfusion measurements during hyperthermia therapy. In: Gerner EW, editor. Hyperthermic Oncology 1992. Vol.I. Tucson: Arizona Board of Regents; 1992. p A17.
65. Rau B, Wust P, Tilly W, Gellermann J, Harder C, Riess H, Budach V, Felix R, Schlag PM. Preoperative radiochemotherapy in locally advanced or recurrent rectal cancer: Regional radiofrequency hyperthermia correlates with clinical parameters. Int J Radiat Oncol Biol Phys 2000;48: 381-391.
66. Lüdemann L, Sreenivasa G, Amthauer H, Michel R, Gellermann J, Wust P. Use of H2 15O-PET for investigating perfusion changes in pelvic tumors due to regional hyperthermia. Int J Hyperthermia 2009;25:299-308.
67. Acker JC, Dewhirst MW, Honoré GM, Samulski TV, Tucker JA, Oleson JR. Blood perfusion measurements in human tumours: Evaluation of laser Doppler methods. Int J Hyperthermia 1990;6:287-304.
68. Molls M, Feldmann HJ. Clinical investigations of blood flow in malignant tumors of the pelvis and the abdomen in patients undergoing thermoradiotherapy. Funktionsanalyse biolog Systeme 1991;20:143-153
69. Waterman FM, Komarnicky L, Leeper DB. The response of human tumour blood flow to a fractionated course of thermoradiotherapy. Int J Hyperthermia 1998;14:421-434.
70. Vaupel P. Pathophysiological effects of hyperthermia in solid tumors and their clinical implication. In: Omlor GH, Vaupel P, Alexander Chr, editors. Isolated Hyperthermic Limb Perfusion. Berlin, Heidelberg, New York: Springer; 1995. pp 9-45.
71. Lyng H, Vorren AO, Sundfør K, Taksdal I, Lien HH, Kaalhus O, Rofstad EK. Intra- and intertumor heterogeneity in blood perfusion of human cervical cancer before treatment and after radiotherapy. Int J Cancer 2001;96:182-190.
72. Kershaw LE, Logue JP, Hutchinson CE, Clarke NW, Buckley DL. Late tissue effects following radiotherapy and neoadjuvant hormone therapy of the prostate measured with quantitative resonance imaging. Radiother Oncol 2008;88: 127-134.
73. Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269-270.
74. Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007;9:1221-1235.
75. Vaupel P, Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev 2007;26:225-239.
76. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: Role of hypoxia and anemia. Med Oncol 2001;18:243-259.
77. Gerweck LE, Urano M, Koutcher J, Fellenz MP, Kahn J. Relationship between energy status, hypoxic cell fraction, and hyperthermic sensitivity in a murine fibrosarcoma. Radiat Res 1989;117:448-458.
78. Overgaard J, Bichel P. The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitro. Radiology 1977;123:511-514.
79. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 2004;9:S10-S17.
80. Giaccia AJ. Hypoxic stress proteins: Survival of the fittest. Semin Radiat Oncol 1996;6:46-58.
81. Höckel M, Vaupel P. Tumor hypoxia: Definitions and current clinical, biologic and molecular aspects. J Natl Cancer Inst 2001;93:266-276.
82. Rofstad EK, Sundfør K, Lyng H, Trope CG. Hypoxiainduced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hxpoxia-induced radiation resistance rather than hypoxia-induced metastasis. Br J Cancer 2000;83:354-359.
83. Rofstad EK, Galappathi K, Mathiesen B, Ruud EB. Fluctuating and diffusion-limited hypoxia in hypoxia-induced metastasis. Clin Cancer Res 2007;13:1971-1978.
84. Cairns RA, Hill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 2004;64: 2054-2061.
85. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev 2007;26:333-339.
86. Chan DA, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev 2004;23:293-310.
87. Bicher HI, Hetzel FW, Sandhu TS, Frinak S, Vaupel P, O'Hara MD, O'Brien T. Effects of hyperthermia on normal and tumor microenvironment. Radiology 1980;137:523-530.
88. Vaupel P, Ostheimer K, Mueller-Klieser W. Circulatory and metabolic responses of malignant tumors during localized hyperthermia. J Cancer Res Clin Oncol 1980;98:15-29.
89. Vaupel P, Otte J, Manz R. Changes in tumor oxygenation after localized microwave hyperthermia. Progr Clin Biol Res 1982;107:65-74.
90. Horsman MR, Overgaard J. Can mild hyperthermia improve tumour oxygenation? Int J Hyperthermia 1997;13: 141-147.
91. Sun X, Li X-F, Russell J, Xing L, Urano M, Li GC, Humm JL, Ling CC. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry. Radiother Oncol 2008;88:269-276.
92. Horsman MR. Tissue physiology and the response to heat. Int J Hyperthermia 2006;22:197-203.
93. Thews O, Li Y, Kelleher DK, Chance B, Vaupel P. Microcirculatory function, tissue oxygenation, microregional redox status and ATP distribution in tumors upon localized infrared-A hyperthermia at 42°C. Adv Exp Med Biol 2003;530:237-247.
94. Kelleher DK, Vaupel P. No sustained improvement in tumor oxygenation after localized mild hyperthermia. Adv Exp Med Biol 2010;662:393-398.
95. Song CW, Shakil A, Griffin RJ, Okajima K. Improvement of tumor oxygenation status by mild temperature hyperthermia alone or in combination with carbogen. Semin Oncol 1997;24:626-632.
96. Song CW, Shakil A, Osborn JL, Iwata K. Tumor oxygenation is increased by hyperthermia at mild temperatures. Int J Hyperthermia 2009;25:91-95.
97. Song C, Park H, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia 2005;21:761-767.
98. Iwata K, Shakil A, Hur WJ, Makepiece CM, Griffin RJ, Song CW. Tumour pO2 can be increased markedly by mild hyperthermia. Br J Cancer Suppl 1996;27:S217-S221. (Pubitemid 26237965)
99. Hetzel FW, Chopp M, Dereski MO. Variations in pO2 and pH response to hyperthermia: Dependence on transplant site and duration of treatment. Radiat Res 1992;131: 152-156.
100. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Dodge RK, Charles HC, Samulski TV, Prosnitz LR, Dewhirst MW. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 1996;56:5347-5350.
101. Vujaskovic Z, Rosen EL, Blackwell KL, Jones EL, Brizel DM, Prosnitz LR, Samulski TV, Dewhirst MW. Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment. Int J Hyperthermia 2003;19: 498-506.
102. Zywietz F, Reeker W, Kochs E. Changes in tumor oxygenation during a combined treatment with fractionated irradiation and hyperthermia: An experimental study. Int J Radiat Oncol Biol Phys 1997;37:155-162.
103. Warburg O. Über den Stoffwechsel der Carcinomzelle. Klin Wschr 1925;4:534-536.
104. Warburg O. The Metabolism of Tumours. London: Constable; 1930.
105. Thistlethwaite AJ, Leeper DB, Moylan DJ, Nerlinger RE. pH distribution in human tumors. Int J Radiat Oncol Biol Phys 1985;11:1647-1652.
106. van den Berg AP, Wike-Hooley JL, van den Berg-Blok AE, van der Zee J, Reinhold HS. Tumour pH in human mammary carcinoma. Eur J Cancer Clin Oncol 1982;18: 457-462.
107. Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984;2:343-366.
108. Kallinowski F, Vaupel P. pH distributions in spontaneous and isotransplanted rat tumors. Br J Cancer 1988;58: 314-321.
109. Kallinowski F, Vaupel P. Factors governing hyperthermiainduced pH changes in malignant tumors. Int J Hyperthermia 1989;5:641-652.
110. Vaupel P, Schaefer C, Okunieff P. Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total Pi. NMR Biomed 1994;7:128-136.
111. Stubbs M, McSheehy PMJ, Griffiths JR, Bashford CL. Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 2000;6:15-19.
112. Tannock IF, Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 1989;49: 4373-4384.
113. Newell K, Tannock I. Regulation of intracellular pH and viability of tumor cells. Funktionsanalyse biolog Systeme 1991;20:219-234.
114. Griffiths JR. Are cancer cells acidic? Br J Cancer 1991;64:425-427.
115. Gerweck LE. Tumor pH: Implications for treatment and novel drug design. Sem Radiat Oncol 1998;8:176-182.
116. Song CW, Lyons JC, Luo Y. Intra- and extracellular pH in solid tumors: Influence on therapeutic response. In: Teicher BA, editor. Drug Resistance in Oncology. New York, Basel, Hong Kong: Marcel Dekker; 1993. pp 25-51.
117. Song CW, Park H, Ross BD. Intra- and extracellular pH in solid tumors. In: Teicher BA, editor. Antiangiogenic Agents in Cancer Therapy. Totowa: Humana Press; 1999. pp 51-64.
118. Prescott DM, Charles CH, Poulson JM, Page RL, Thrall DE, Vujaskovic Z, Dewhirst MW. The relationship between intracellular and extracellular pH in spontaneous canine tumors. Clin Cancer Res 2000;6: 2501-2505.
119. Stubbs M, Bhujwalla ZM, Tozer GM, Rodrigues LM, Maxwell RJ, Morgan R, Howe FA, Griffiths JR. An assessment of 31P-MRS as a method of measuring pH in rat tumours. NMR Biomed 1992;5:351-359.
120. Gerweck LE. Modifiers of thermal effects: Environmental factors. In: Urano M, Douple E, editors. Hyperthermia and Oncology. Vol.1. Utrecht: VSP; 1988. pp 83-98.
121. van der Zee J, Broekmeyer-Reurink MP, van den Berg AP, van Geel BN, Jansen RMF, Kroon BBR, van Wyk J, Hagenbeck A. Temperature distribution and pH changes during hyperthermic regional isolation perfusion. Eur J Cancer Clin Oncol 1989;25:1157-1163.
122. van de Merwe SA, van den Berg AP, van der Zee J, Reinhold HS. Measurement of tumor pH during microwave induced experimental and clinical hyperthermia with a fiber optic pH measurement system. Int J Radiat Oncol Biol Phys 1990;18:51-57.
123. Lora-Michiels M, Yu D, Sanders L, Poulson JM, Azuma C, Case B, Vujaskovic Z, Thrall DE, Charles HC, Dewhirst MW. Extracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapy. Clin Cancer Res 2006;12:5733-5740.
124. Engin K, Leeper DB, Thistlethwaite AJ, Tupchong L, McFarlane JD. Tumor extracellular pH as a prognostic factor in thermoradiotherapy. Int J Radiat Oncol Biol Phys 1994;30:125-132.
125. van den Berg AP, Wike-Hooley JL, Broekmeyer-Reurink MP, van der Zee J, Reinhold HS. The relationship between the unmodified initial tissue pH of human tumours and the response to combined radiotherapy and local hyperthermia treatment. Eur J Cancer Clin Oncol 1989;25:73-78.
126. Vaupel P, Kelleher DK, Engel T. Stable bioenergetic status despite substantial changes in blood flow and tissue oxygenation in a rat tumour. Br J Cancer 1994;69:46-49.
127. Gerweck LE, Dahlberg WK, Epstein LF, Shimm D. Influence of nutrient and energy deprivation on cellular response to single and fractionated heat treatments. Radiat Res 1984;99:573-581.
128. Koutcher JA, Barnett D, Kornblith AB, Cowburn D, Brady TJ, Gerweck LE. Relationship of changes in pH and energy status to hypoxic cell fraction and hyperthermia sensitivity. Int J Radiat Oncol Biol Phys 1990;18:1429-1435.
129. Sijens PE, Bovee WMMJ, Koole P, Schipper J. Phosphorus NMR study of the response of a murine tumour to hyperthermia as a function of treatment time and temperature. Int J Hyperthermia 1989;5:351-357.
130. Vaupel P, Okunieff P, Neuringer LJ. In vivo 31P-NMR spectroscopy of murine tumours before and after localized hyperthermia. Int J Hyperthermia 1990;6:15-31.
131. Dewhirst MW, Poulson JM, Yu D, Sanders L, Lora- Michiels M, Vujaskovic Z, Jones EL, Samulski TV, Powers BE, Brizel DM, et al. Relation between pO2, 31P magnetic resonance spectroscopy parameters and treatment outcome in patients with high-grade soft tissue sarcomas treated with thermoradiotherapy. Int J Radiat Oncol Biol Phys 2005;61:480-491.