Tumor hypoxia and therapeutic resistance

  • Peter Vaupel
  • Michael Höckel


For many years, the identification of tumor hypoxia, its systematic characterization and the assessment of its clinical relevance were not possible due to the lack of methods suitable for the routine measurement of intratumoral oxygen tensions in patients. In the late 1980s, a novel and clinically applicable standardized procedure was established enabling the determination of tumor oxygenation in accessible primary tumors, local recurrences, and metastatic lesions in patients using a computerized polarographic needle electrode system (Vaupel et al. 1991; Höckel et al. 1991). Within a relatively short period of time, the significance of tumor oxygenation for therapy outcome became evident in numerous experimental and clinical studies (for a review see Vaupel and Kelleher 1999).


Uterine Cervix Oxygenation Status Tumor Hypoxia Squamous Cell Carcinoma Therapeutic Resistance 
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  1. Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR, Sutherland RM (1994) Regulation of c-jun expression during hypoxic and low-glucose stress. Mol Cell Biol 14: 5032–5042PubMedGoogle Scholar
  2. Awwad HK, Naggar M, Mocktar N, Barsoum M (1986) Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri. Int J Radiat Oncol Biol Phys 12: 1329–1333PubMedCrossRefGoogle Scholar
  3. Brizel DM, Scully SP, Harrelson TM, Layfield LJ, Bean JM, Prosnitz LR, Dewhirst MW (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56: 941–943PubMedGoogle Scholar
  4. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW (1997) Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38: 285–289PubMedCrossRefGoogle Scholar
  5. Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res 58: 1408–1416PubMedGoogle Scholar
  6. Bush RS (1986) The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 12: 2047–2050PubMedCrossRefGoogle Scholar
  7. Chabner B, Allegra CJ, Curt GA, Calabresi P (1996) Antineoplastic agents. In: Goodman & Gilman’s (eds) The Pharmacological basis of therapeutics. 9th edn. McGraw-Hill, New York, pp 1233–1287Google Scholar
  8. Chaplin DJ, Horsman MR, Trotter MJ, Siemann DW (2000) Therapeutic significance of microenvironmental factors. In: Molls M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors. Implications for clinical radiooncology. Springer, Berlin Heidelberg New York, pp 133–143Google Scholar
  9. Chapman JD, Stobbe CC, Arnfield MR, Santus R, Lee L, McPhee MS (1991) Oxygen dependency of tumor cell killing in vitro by light-activated Photofrin II. Radiat Res 126: 73–79PubMedCrossRefGoogle Scholar
  10. Cheng KC, Loeb LA (1993) Genomic instability and tumor progression: mechanistic considerations. Adv Cancer Res 60: 121–156PubMedCrossRefGoogle Scholar
  11. Collingridge DR, Piepmeier JM, Rockwell S, Knisely JPS (1999) Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol 53: 127–131PubMedCrossRefGoogle Scholar
  12. Dachs GU, Tozer GM (2000) Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer 36: 1649–1660PubMedCrossRefGoogle Scholar
  13. Durand RE (1991) Keynote address: The influence of microenvironmental factors on the activity of radiation and drugs. Int J Radiat Oncol Biol Phys 20: 253–258PubMedCrossRefGoogle Scholar
  14. Durand RE (1994) The influence of microenvironmental factors during cancer therapy. In Vivo 8: 691–702Google Scholar
  15. Erlichman C (1992) Pharmacology of anticancer drugs. In: Tannock IF, Hill RP (eds) The basic science of oncology, 2’ edn. McGraw-Hill, New York, pp 317–337Google Scholar
  16. Freitas I, Baronzio GF (1991) Tumor hypoxia, reoxygenation and oxygenation strategies: possible role in photodynamic therapy. J Photochem Photobiol B: Biol 11: 3–30CrossRefGoogle Scholar
  17. Frommhold H, Guttenberger R, Henke M (1998) The impact of blood hemoglobin content on the outcome of radiotherapy. Strahlenther Onkol 174 (Suppl IV): 31–34PubMedGoogle Scholar
  18. Fyles AW, Milosevic M, Wong R, Kavanagh M-C, Pintilie M, Sun A, Chapman W, Levin W, Manchul L, Keane TJ, Hill RP (1998) Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48: 149–156PubMedCrossRefGoogle Scholar
  19. Giaccia AJ (1996) Hypoxic stress proteins: survival of the fittest. Semin Radiat Oncol 6: 46–58PubMedCrossRefGoogle Scholar
  20. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379: 88–91PubMedCrossRefGoogle Scholar
  21. Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Giaccia AJ (1994) Hypoxia induces accumulation of p53 protein, but activation of a GI-phase checkpoint by low-oxygen conditions is independent of p53 status. Molecular Cell Biol 14: 6264–6277CrossRefGoogle Scholar
  22. Grau C, Overgaard J (2000) Significance of hemoglobin concentration for treatment outcome. In: Molls M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors. Implications for Clinical Radiooncology. Springer, Berlin Heidelberg New York, pp 101–112Google Scholar
  23. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OCA (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26: 638–648PubMedCrossRefGoogle Scholar
  24. Hall EJ (2000) Radiobiology for the radiologist 5th edn. Lippincott, PhiladelphiaGoogle Scholar
  25. Henderson BW, Fingar VH (1987) Relationship of tumor hypoxia and response to photodynamic treatment in an experimental mouse tumor. Cancer Res 47: 3110–3114PubMedGoogle Scholar
  26. Henke M, Momm F, Guttenberger R (1999) Erythropoietin for patients undergoing radiotherapy: The Freiburg experience. In: Vaupel P, Kelleher DK (eds) Tumor hypoxia. Pathophysiology, clinical significance and therapeutical perspectives. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 91–97Google Scholar
  27. Hickman JA, Potten CS, Merritt AJ, Fisher TC (1994) Apoptosis and cancer chemotherapy. Phil Trans R Soc B 345: 319–325PubMedCrossRefGoogle Scholar
  28. Höckel M, Vaupel P (2001a) Tumor hypoxia: Definitions and current clinical, biological and molecular aspects. J Natl Cancer Inst 93: 266–276PubMedCrossRefGoogle Scholar
  29. Höckel M, Vaupel P (2001b) Prognostic significance of tissue hypoxia in cervical cancer. CME J Gynecol Oncol 6: 216–225Google Scholar
  30. Höckel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50PubMedCrossRefGoogle Scholar
  31. Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U, Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515PubMedGoogle Scholar
  32. Höckel M, Schlenger K, Höckel S, Aral B, Schäffer U, Vaupel P (1998) Tumor hypoxia in pelvic recurrences of cervical cancer. Int J Cancer 79: 365–369PubMedCrossRefGoogle Scholar
  33. Höckel M, Schlenger K, Höckel S, Vaupel P (1999) Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res 59: 4525–4528PubMedGoogle Scholar
  34. Hoeckel M, Schlenger K, Knoop C, Vaupel P (1991) Oxygenation of carcinomas of the uterine cervix: Evaluation of computerized O2 tension measurements. Cancer Res 51: 6098–6102Google Scholar
  35. Kallinowski F, Buhr HJ (1995) Tissue oxygenation of primary, metastatic and xenografted rectal cancers. In: Vaupel P, Kelleher DK, Günderoth M (eds) Tumor oxygenation. Fischer, Stuttgart, pp 205–209Google Scholar
  36. Kelleher DK, Thews O, Vaupel P (1999) Modulation of tumor oxygenation and radiosensitivity by erythropoietin. In: Vaupel P, Kelleher DK (eds) Tumor hypoxia. Pathophysiology, clinical significance and therapeutic perspectives, Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 83–90Google Scholar
  37. Kim CY, Tsai MH, Osmanian C, Graeber TG, Lee JE, Giffard RG, DiPaolo JA, Peehl DM, Giaccia AJ (1997) Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions. Cancer Res 57: 4200–4204PubMedGoogle Scholar
  38. Knocke TH, Weitmann H-D, Feldmann H-J, Selzer E, Pötter R (1999) Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiother Oncol 53: 99–104PubMedCrossRefGoogle Scholar
  39. Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M (2000) Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 48: 919–922PubMedCrossRefGoogle Scholar
  40. Kumar P (2000) Tumor hypoxia and anemia: Impact on the efficacy of radiation therapy. Semin Hematol 37 (Suppl 6): 4–8PubMedCrossRefGoogle Scholar
  41. Laderoute KR, Grant TD, Murphy BJ, Sutherland RM (1992) Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen. Int J Cancer 52: 428–432PubMedCrossRefGoogle Scholar
  42. Lartigau E, Randrianarivelo H, Avril M-F, Margulis A, Spatz A, Eschwege F, Guichard M (1997) Intratumoral oxygen tension in metastatic melanoma. Melanoma Res 7: 400–406PubMedCrossRefGoogle Scholar
  43. Lavey RS (1999) Clinical trial experience using erythropoietin during radiation therapy. In: Vaupel P, Kelleher DK (eds) Tumor hypoxia. Pathophysiology, clinical significance and therapeutic perspectives. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 99–105Google Scholar
  44. Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CML (2000) Vascular endothelial growth factor ( VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer 83: 620–625PubMedCrossRefGoogle Scholar
  45. Mattem J, Kallinowski F, Herfarth C, Volm M (1996) Association of resistance-related protein expression with poor vascularization and low levels of oxygen in human rectal cancer. Int J Cancer 67: 20–23CrossRefGoogle Scholar
  46. Mayr NA, Yuh WTC, Magnotta VA, Ehrhardt JC, Wheeler JA, Sorosky JI, Davis CS, Wen B-C, Martin DD, Pelsang RE, Buller RE, Oberley LW, Mellenberg DE, Hussey DH (1996) Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay. Int J Radiat Oncol Biol Phys 36: 623–633PubMedCrossRefGoogle Scholar
  47. Mitchell JB, McPherson S, De Graff W, Gamson J, Zabell A, Russo A (1985) Oxygen dependence of hematoporphyrin derivative-induced photo-inactivation of Chinese hamster cells. Cancer Res 45: 2008–2011PubMedGoogle Scholar
  48. Moan J, Sommer S (1985) Oxygen dependence of the photosensitizing effect of hematoporphyrin derivative in NHIK 3025 cells. Cancer Res 45: 1608–1610PubMedGoogle Scholar
  49. Moulder JE, Rockwell S (1987) Tumor hypoxia: its impact on cancer therapy. Cancer Metast Rev 5: 313–341CrossRefGoogle Scholar
  50. Movsas B, Chapman JD, Greenberg RE, Hanlon AL, Horwitz EM, Pinover WH, Stobbe C, Hanks GE (2000) Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age. Cancer 89: 2018–2024PubMedCrossRefGoogle Scholar
  51. Movsas B, Chapman JD, Horwitz EM, Pinover WH, Greenberg RE, Hanlon AL, Iyer R, Hanks GE (1999) Hypoxic regions exist in human prostate carcinoma. Urology 53: 11–18PubMedCrossRefGoogle Scholar
  52. Nordsmark M, Overgaard J (2000) A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol 57: 39–43PubMedCrossRefGoogle Scholar
  53. Nordsmark M, Hoyer M, Keller J, Nielsen OS, Jensen OM, Overgaard J (1996) The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 35: 701–708PubMedCrossRefGoogle Scholar
  54. Nordsmark M, Keller J, Nielsen OS, Lundorf E, Overgaard J (1997) Tumour oxygenation assessed by polarographic needle electrodes and bioenergetic status measured by 31P magnetic resonance spectroscopy in human soft tissue tumours. Acta Oncol 36: 565–571PubMedCrossRefGoogle Scholar
  55. Raleigh JA (ed)(1996) Hypoxia and its clinical significance. Semin Radiat Oncol 6: 1–70Google Scholar
  56. Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA, Workman P (1994) Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int J Radiat Oncol Biol Phys 29: 427–432PubMedCrossRefGoogle Scholar
  57. Révész L, Sirackâ E, Sirackÿ J, Delides G, Pavlaki K (1989) Variation of vascular density within and between tumors of the uterine cervix and its predictive value for radiotherapy. Int J Radiat Oncol Biol Phys 16: 1161–1163PubMedCrossRefGoogle Scholar
  58. Reynolds TY, Rockwell S, Glazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Res 56: 5754–5757PubMedGoogle Scholar
  59. Rice GC, Hoy C, Schimke RT (1986) Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 83: 5978–5982PubMedCrossRefGoogle Scholar
  60. Russo CA, Weber TK, Volpe CM, Stoler DL, Petrelli NJ, Rodriguez-Bigas M, Burhans WC, Anderson GR (1995) An anoxia inducible endonuclease and enhanced DNA breakage as contributors to genomic instability in cancer. Cancer Res 55: 1122–1128PubMedGoogle Scholar
  61. Sakata K, Kwok TT, Murphy BJ, Laderoute KR, Gordon GR, Sutherland RM (1991) Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br J Cancer 64: 809–814PubMedCrossRefGoogle Scholar
  62. Sanna K, Rofstad EK (1994) Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int J Cancer 58: 258–262PubMedCrossRefGoogle Scholar
  63. Semenza GL (2000a) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Molec Biol 35: 71–103CrossRefGoogle Scholar
  64. Semenza GL (2000b) HIF-1: mediator of physiological and pathophysiological response to hypoxia. J Appl Physiol 88: 1474–1480PubMedGoogle Scholar
  65. Silver DF, Piver MS (1999) Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: a possible oxygen effect. Gynecol Oncol 73: 280–284PubMedCrossRefGoogle Scholar
  66. Sirackâ E, Révész L, Kovâc R, Sirackÿ J (1988) Vascular density in carcinoma of the uterine cervix and its predictive value for radiotherapy. Int J Cancer 41: 819–822PubMedCrossRefGoogle Scholar
  67. Song CW, Lyons JC, Luo Y (1993) Intracellular pH in solid tumors: Influence on therapeutic response. In: Teicher BA (ed) Drug resistance in oncology. Marcel Dekker, New York, pp 25–51Google Scholar
  68. Stackpole CW, Groszek L, Kalbag SS (1994) Benign-to-malignant B16 melanoma progression induced in two stages in vitro by exposure to hypoxia. J Natl Cancer Inst 86: 361–367PubMedCrossRefGoogle Scholar
  69. Stadler P, Becker A, Feldmann HJ, Hänsgen G, Dunst J, Würschmidt, Molls M (1999) Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol 44: 749–754CrossRefGoogle Scholar
  70. Stoler DL, Anderson GR, Russo CA, Spina AM, Beerman TA (1992) Anoxia-inducible endonuclease activity as a potential basis of the genomic instability of cancer cells. Cancer Res 52: 4372–4378PubMedGoogle Scholar
  71. Sundfor K, Lyng H, Rofstad EK (1998) Oxygen tension and vascular density in adenocarcinoma and squamous cell carcinoma of the uterine cervix. Acta Oncol 37: 665–670PubMedCrossRefGoogle Scholar
  72. Sundfor K, Lyng H, Trope CG, Rofstad EK (2000) Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. Radiother Oncol 54: 101–107PubMedCrossRefGoogle Scholar
  73. Sutherland RM (1998) Tumor hypoxia and gene expression. Implications for malignant progression and therapy. Acta Oncol 37: 567–574PubMedCrossRefGoogle Scholar
  74. Tannock IF, Hill RP (eds)(1992) The basic science of oncology, 2nd edn. McGraw-Hill, New YorkGoogle Scholar
  75. Teicher BA (ed)(1993) Drug resistance in oncology. Marcel Dekker, New YorkGoogle Scholar
  76. Teicher BA (1994) Hypoxia and drug resistance. Cancer Metast Rev 13: 139–168CrossRefGoogle Scholar
  77. Teicher BA (1995) Physiologic mechanisms of therapeutic resistance. Blood flow and hypoxia. Hematol Oncol Clin North Am 9: 475–506PubMedGoogle Scholar
  78. Teicher BA, Lazo JS, Sartorelli AC (1981) Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res 41: 73–81PubMedGoogle Scholar
  79. Teicher BA, Holden SA, Al-Achi A, Herman TS (1990) Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaII murine fibrosarcoma. Cancer Res 50: 3339–3344PubMedGoogle Scholar
  80. Thews O, Kelleher DK, Vaupel P (2001) Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res 61: 1358–1361PubMedGoogle Scholar
  81. Thews O, Koenig R, Kelleher DK, Kutzner J, Vaupel P (1998) Enhanced radio-sensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 78: 752–756PubMedCrossRefGoogle Scholar
  82. Vaupel P (1994) Blood flow, oxygenation, tissue pH distribution and bioenergetic status of tumors. Ernst Schering Research Foundation, Lecture 23, BerlinGoogle Scholar
  83. Vaupel P (1997a) Blood flow and oxygenation status of head and neck carcinomas. Adv Exp Med Biol 428: 89–95PubMedCrossRefGoogle Scholar
  84. Vaupel P (1997b) The influence of tumor blood flow and microenvironmental factors on the efficacy of radiation, drugs and localized hyperthermia. Klin Pädiatr 209: 243–249PubMedCrossRefGoogle Scholar
  85. Vaupel P (2001) Durchblutung and Oxygenierungsstatus von Kopf-Hals-Tumoren. In: Böttcher HD, Wendt TG, Henke M (Hrsg) Klinik des Rezidivtumors im KopfHals-Bereich. Grundlagen–Diagnostik–Therapie. Zuckschwerdt, München, Bern, Wien, New York, pp 7–23Google Scholar
  86. Vaupel P, Höckel M (1999) Oxygenation status of breast cancer: The Mainz experience. In: Vaupel P, Kelleher DK (eds) Tumor hypoxia. Pathophysiology, clinical significance and therapeutic perspectives. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 1–11Google Scholar
  87. Vaupel P, Höckel M (2000) Blood supply, oxygenation status and metabolic micro-milieu of breast cancers: Characterization and therapeutic relevance. Int J Oncol 17: 869–879PubMedGoogle Scholar
  88. Vaupel P, Höckel M (2001) Hypoxie beim Zervixkarzinom: Pathogenese, Charakterisierung und biologische/klinische Konsequenzen. Zentralbl Gynäkol 123: 192–197PubMedCrossRefGoogle Scholar
  89. Vaupel P, Kelleher DK (eds) (1999) Tumor hypoxia: Pathophysiology, clinical significance and therapeutic perspectives. Wissenschaftliche Verlagsgesellschaft, StuttgartGoogle Scholar
  90. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 49: 6449–6465PubMedGoogle Scholar
  91. Vaupel P, Schienger K, Knoop C, Hoeckel M (1991) Oxygenation of human tumors: Evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51: 3316–3322PubMedGoogle Scholar
  92. Vera JC, Castillo GR, Rosen OM (1991) A possible role for a mammalian facilitative hexose transporter in the development of resistance to drugs. Mol Cell Biol 11: 3407–3418PubMedGoogle Scholar
  93. Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci USA 85: 9533–9537PubMedCrossRefGoogle Scholar
  94. Zeller WJ (1995) Bleomycin. In: Zeller WJ, zur Hausen H (Hrsg) Onkologie: Grundlagen, Diagnostik, Therapie, Entwicklungen. ecomed, Landsberg, pp IV-3. 12, 1–7Google Scholar

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© Springer-Verlag/Wien 2002

Authors and Affiliations

  1. 1.Institute of Physiology and PathophysiologyUniversity of MainzMainzGermany
  2. 2.Department of Obstetrics and GynecologyUniversity of LeipzigLeipzigGermany

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