Skip to main content
SpringerLink
Log in

Treatment resistance of solid tumors

Role of hypoxia and anemia

  • Review
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Hypoxia is a characteristic property of locally advanced solid tumors, resulting from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the development of hypoxia are (1) structural and functional abnormalities of the tumor microvasculature, (2) increased diffusion distances, and (3) tumor-associated and therapy-induced anemia. The oxygenation status is independent of clinical tumor size, stage, grade, and histopathological type, but is affected by the hemoglobin level. Hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Hypoxia and anemia (most probably via worsening of tumor hypoxia) can lead to therapeutic problems, as they make solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. In addition to more direct mechanisms involved in the development of therapeutic resistance, there are also indirect machineries that can cause barriers to therapies. These include hypoxia-driven proteome and genome changes and clonal selection. These, in turn, can drive subsequent events that are known to further increase resistance to therapy (in addition to critically affecting long-term prognosis). Treatment resistance in anemic patients can be, at least partially, prevented or overcome by anemia correction, resulting in better locoregional tumor control and overall survival of patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vaupel, P., Schlenger, K., Knoop, C. and Hoeckel, M. (1991). Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 51:3316–3322.

    PubMed  CAS  Google Scholar 

  2. Hoeckel, M., Schlenger, K., Knoop, C. and Vaupel, P. (1991). Oxygenation of carcinomas of the uterine cervix: evaluation of computerized O2 tension measurements. Cancer Res. 51:6098–6102.

    Google Scholar 

  3. Vaupel, P. and Kelleher, D. K. (eds). (1999). Tumor Hypoxia. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  4. Höckel, M. and Vaupel, P. (2001). Tumor hypoxia: definitions and current clinical, biological and molecular aspects. J. Natl. Cancer Inst. 93:266–276.

    Article  PubMed  Google Scholar 

  5. Höckel, M., et al. (1993). Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother. Oncol. 26:45–50.

    Article  PubMed  Google Scholar 

  6. Höckel, M., et al. (1996). Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56:4509–4515.

    PubMed  Google Scholar 

  7. Höckel, M., Schlenger, K., Höckel, S. and Vaupel, P. (1999). Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 59:4525–4528.

    PubMed  Google Scholar 

  8. Sundfor, K., Lyng, H. and Rofstad, E. K. (1998). Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br. J. Cancer 78:822–827.

    PubMed  CAS  Google Scholar 

  9. Fyles, A. W., et al. (1998). Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother. Oncol. 48:149–156.

    Article  PubMed  CAS  Google Scholar 

  10. Knocke, T. H., Weitmann, H.-D., Feldmann, H.-J., Selzer, E. and Pötter, S. (1999). Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiother. Oncol. 53:99–104.

    Article  PubMed  CAS  Google Scholar 

  11. Sundfor, K., Lyng, H., Tropé, C. G. and Rofstad, E. K. (2000). Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. Radiother. Oncol. 54:101–107.

    Article  PubMed  CAS  Google Scholar 

  12. Nordsmark, M., Overgaard, M. and Overgaard, J. (1996). Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 41:31–39.

    PubMed  CAS  Google Scholar 

  13. Brizel, D. M., Sibley, G. S., Prosnitz, L. R., Scher, R. L. and Dewhirst, M. W. (1997). Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 38:285–289.

    Article  PubMed  CAS  Google Scholar 

  14. Stadler, P., et al. (1999). Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 44:749–754.

    Article  PubMed  CAS  Google Scholar 

  15. Nordsmark, M. and 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. 57:39–43.

    Article  PubMed  CAS  Google Scholar 

  16. Brizel, D. M., et al. (1996). Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56:941–943.

    PubMed  CAS  Google Scholar 

  17. Rampling, R., Cruickshank, G., Lewis, A. D., Fitzsimmons, S. A. and Workman, P. (1994). Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 29:427–431.

    PubMed  CAS  Google Scholar 

  18. Collingridge, D. R., Piepmeier, J. M., Rockwell, S. and Knisely, J. P. S. (1999). Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother. Oncol. 53:127–131.

    Article  PubMed  CAS  Google Scholar 

  19. Movsas, B., et al. (1999). Hypoxic regions exist in human prostate carcinoma. Urology 53:11–18.

    Article  PubMed  CAS  Google Scholar 

  20. Movsas, B., et al. (2000). Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age. Cancer 89:2018–2024.

    Article  PubMed  CAS  Google Scholar 

  21. Aquino-Parsons, C., Green, A. and Minchinton, A. I. (2000). Oxygen tension in primary gynaecological tumours: the influence of carbon dioxide concentration. Radiother. Oncol. 57:45–51.

    Article  PubMed  CAS  Google Scholar 

  22. Lyng, H., Sundfor, K. and Rofstad, E. K. (2000). Changes in tumor oxygen tension during radiotherapy of uterine cervical cancer: relationships to changes in vascular density, cell density, and frequency of mitosis and apoptosis. Int. J. Radiat. Oncol. Biol. Phys. 46:935–946.

    Article  PubMed  CAS  Google Scholar 

  23. Dunst, J., Hänsgen, G., Lautenschläger, C., Füchsel, G. and Becker, A. (1999). Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon. Int. J. Radiat. Oncol. Biol. Phys. 43:367–373.

    Article  PubMed  CAS  Google Scholar 

  24. Becker, A., et al. (2000). Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 46:459–466.

    Article  PubMed  CAS  Google Scholar 

  25. Lartigau, E., et al. (1997). Intratumoral oxygen tension in metastatic melanoma. Melanoma Res. 7:400–406.

    Article  PubMed  CAS  Google Scholar 

  26. Becker, A., et al. (1998). Oxygenation of squamous cell carcinoma of the head and neck: comparison of primary tumors, neck node metastases, and normal tissue. Int. J. Radiat. Oncol. Biol. Phys. 42:35–41.

    Article  PubMed  CAS  Google Scholar 

  27. Vaupel, P. (2001). Durchblutung und Oxygenierungsstatus von Kopf-Hals-Tumoren, in Klinik des Rezidivtumors im Kopf-Hals-Bereich. Grundlagen — Diagnostik — Therapie. (H. D., Böttcher, T. G., Wendt, M. Henke, hrsg), pp 7–23. Zuckschwerdt, München.

    Google Scholar 

  28. Haensgen, G., et al. (2001). Tumor hypoxia, p53, and prognosis in cervical cancers. Int. J. Radiat. Oncol. Biol. Phys. 50:865–872.

    Article  PubMed  CAS  Google Scholar 

  29. Nordsmark, M., et al. (2001). Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 49:581–586.

    Article  PubMed  CAS  Google Scholar 

  30. Evans, S. M., et al. (2001). Hypoxia in human intraperitoneal and extremity sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 49:587–596.

    Article  PubMed  CAS  Google Scholar 

  31. Nordsmark, M., et al. (2001). Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br. J. Cancer 84:1070–1075.

    Article  PubMed  CAS  Google Scholar 

  32. Vaupel, P., Kelleher, D. K. and Höckel, M. (2001). Oxgenation status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin. Oncol. 28(Suppl. 8):29–35.

    Article  PubMed  CAS  Google Scholar 

  33. Vaupel, P. and Höckel, M. (2001). Hypoxie beim Zervixkarzinom: Pathogenese, Charakterisierung und biologische/klinische Konsequenzen. Zentralbl. Gynakol. 123:192–197.

    Article  PubMed  CAS  Google Scholar 

  34. 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 

  35. Vaupel, P. W. (1994). Blood flow, oxygenation, tissue pH distribution and bioenergetic status of tumors. Ernst Schering Research Foundation Lecture 23.

  36. Lyng, H., et al. (2001). Intra- and intertumor heterogeneity in blood perfusion of human cervical cancer before treatment and after radiotherapy. Int. J. Cancer 96:182–190.

    Article  PubMed  CAS  Google Scholar 

  37. Jelkmann, W. (2000). Use of recombinant human erythropoietin as an antianemic and performance enhancing drug. Curr. Pharm. Biotech. 1:1–31.

    Google Scholar 

  38. Nowrousian, M. R. (1998). Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy-induced anaemia in patients with solid tumors. Med. Oncol. 15(Suppl. 1):S19-S28.

    PubMed  Google Scholar 

  39. Bron, D., Meuleman, N. and Mascaux, C. (2001). Biological basis of anemia. Semin. Oncol. 28(Suppl. 8):1–6.

    Article  PubMed  CAS  Google Scholar 

  40. Ludwig, H. and Fritze, E. (1998). Anemia in cancer patients. Semin. Oncol. 25:2–6.

    PubMed  CAS  Google Scholar 

  41. Groopman, J. E. and Itri, L. M. (1999). Chemotherapy-induced anemia in adults: incidence and treatment. J. Natl. Cancer Inst. 91:1616–1634.

    Article  PubMed  CAS  Google Scholar 

  42. Groebe, K. (1999). Impact of anemia on the oxygenation status of tumors: a theoretical study, in Tumor Hypoxia. (P. Vaupel and D. K. Kelleher, eds), pp 75–82, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  43. Kelleher, D. K., Matthiensen, U., Thews, O. and Vaupel, P. (1996). Blood flow, oxygenation, and bioenergetic status of tumors after erythropoietin treatment in normal and anemic rats. Cancer Res. 56:4728–4734.

    PubMed  CAS  Google Scholar 

  44. Kelleher, D. K., Matthiensen, U., Thews, O. and Vaupel, P. (1995). Tumor oxygenation in anemic rats: effects of erythropoietin treatment versus red blood cell transfusion. Acta Oncol. 34:379–384.

    PubMed  CAS  Google Scholar 

  45. Vaupel, P., Thews, O., Kelleher, D. K. and Hoeckel, M. (1998). Oxygenation of human tumors: the Mainz experience. Strahlenther. Onkol. 174(Suppl. IV):6–12.

    PubMed  Google Scholar 

  46. Thews, O. and Vaupel, P. (2001). Tumour hypoxia and anaemia: implications for the outcome of radiotherapy and chemotherapy. Focus Anaemia Cancer 2:59–65.

    Google Scholar 

  47. Brizel, D. M. (1999). Human tumor oxygenation: The Duke University Medical Center experience, in Tumor Hypoxia (P. Vaupel and D. K. Kelleher, eds), pp 29–38, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  48. Dunst, J., Feldmann, H. J., Becker, A., Stadler, P., Hänsgen, G. and Molls, M. (1999). Oxygenation of human tumors: the Munich/Halle experience, in Tumor Hypoxia. (P. Vaupel and D. K. Kelleher, eds), pp 39–46, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  49. Durand, R. E. (1991). Keynote address: the influence of microenvironmental factors on the activity of radiation and drugs. Int. J. Radiat. Oncol. Biol. Phys. 20:253–258.

    PubMed  CAS  Google Scholar 

  50. Durand, R. E. (1994). The influence of microenvironmental factors during cancer therapy. In Vivo 8:691–702.

    PubMed  CAS  Google Scholar 

  51. Teicher, B. A. (ed). (1993). Drug Resistance in Oncology. Marcel Dekker, New York.

    Google Scholar 

  52. Teicher, B. A. (1994). Hypoxia and drug resistance. Cancer Metastasis 13:139–168.

    Article  CAS  Google Scholar 

  53. Teicher, B. A. (1995). Physiologic mechanisms of therapeutic resistance. Hematol. Oncol. Clin. North Am. 9:475–506.

    PubMed  CAS  Google Scholar 

  54. Vaupel, P. (1997). The influence of tumor blood flow and microenvironmental factors on the efficacy of radiation, drugs and localized hyperthermia. Klin. Pädiatr. 209:243–249.

    Article  PubMed  CAS  Google Scholar 

  55. Chaplin, D. J., Horsman, M. R., Trotter, M. J. and Siemann, D. W. (2000). Therapeutic significance of microenvironmental factors. in Blood Perfusion and Microenvironment of Human Tumors. Implications for Clinical Radiooncology (M. Molls and P. Vaupel, eds), pp 133–134, Springer-Verlag, Berlin.

    Google Scholar 

  56. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S. and Scott, O. C. A. (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26:638–648.

    Article  PubMed  CAS  Google Scholar 

  57. Evans, J. C. and Bergsjö, P. (1965). The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology 84:709–717.

    PubMed  CAS  Google Scholar 

  58. Bush, R. S. (1986). The significance of anemia in clinical radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 12:2047–2050.

    PubMed  CAS  Google Scholar 

  59. Frommhold, H., Guttenberger, R. and Henke, M. (1998). The impact of blood hemoglobin content on the outcome of radiotherapy. The Freiburg experience. Strahlenther. Onkol. 174(Suppl. 4):31–34.

    PubMed  Google Scholar 

  60. Henke, M., Momm, F. and Guttenberger, R. (1999). Erythropoietin for patients undergoing radiotherapy: the Freiburg experience, in Tumor Hypoxia (P. Vaupel and D. K. Kelleher, eds), pp 91–97, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  61. Grau, C. and Overgaard, J. (2000). Significance of hemoglobin concentration for treatment outcome, in Blood Perfusion and Microenvironment of Human Tumors. Implications for Clinical Radiooncology. (M. Molls and P. Vaupel, eds), pp 101–112, Springer-Verlag, Berlin.

    Google Scholar 

  62. Kumar, P. (2000). Tumor hypoxia and anemia: Impact on the efficacy of radiation therapy. Semin. Hematol. 37:4–8.

    Article  PubMed  CAS  Google Scholar 

  63. Henke, M., Bechtold, C., Momm, F., Dörr, W. and Guttenberger, R. (2000). Blood hemoglobin level may affect radiosensitivity—preliminary results on acutely reacting normal tissues. Int. J. Radiat. Oncol. Biol. Phys. 48:339–345.

    Article  PubMed  CAS  Google Scholar 

  64. Dubray, B., et al. (1996). Anemia is associated with lower local-regional control and survival after radiation therapy for head and neck cancer: a prospective study. Radiology 201:553–558.

    PubMed  CAS  Google Scholar 

  65. Grant, D. G., Hussain, A. and Hurman, D. (1999). Pretreatment anaemia alters outcome in early squamous cell carcinoma of the larynx treated by radical radiotherapy. J. Laryngol. Otol. 113:829–833.

    PubMed  CAS  Google Scholar 

  66. Girinski, T., et al. (1989). Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. Int. J. Radiat. Oncol. Biol. Phys. 16:37–41.

    PubMed  CAS  Google Scholar 

  67. Rudat, V., et al. (1999). Prognostic impact of total tumor volume and hemoglobin concentration on the outcome of patients with advanced head and neck cancer after concomitant boost radiochemotherapy. Radiother. Oncol. 53:119–125.

    Article  PubMed  CAS  Google Scholar 

  68. Thomas, G. (2001). The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience. Semin. Oncol. 28(Suppl. 8):60–65.

    Article  PubMed  CAS  Google Scholar 

  69. Glaser, C., et al. (2001). Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int. J. Radiat. Oncol. Biol. Phys. 50:705–715.

    Article  PubMed  CAS  Google Scholar 

  70. Dietz, A., et al. (2000). Prognostischer Stellenwert des Hämoglobinwertes vor primärer Radiochemotherapy von Kopf-Hals-Karzinomen. HNO 48:655–664.

    Article  PubMed  CAS  Google Scholar 

  71. Lutterbach, J. and Guttenberger, R. (2000). Anemia is associated with decreased local control of surgically treated squamous cell carcinomas of the glottic larynx. Int. J. Radiat. Oncol. Biol. Phys. 48:1345–1350.

    Article  PubMed  CAS  Google Scholar 

  72. Thews, O., Koenig, R., Kelleher, D. K., Kutzner, J. and Vaupel, P. (1998). Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br. J. Cancer 78:752–756.

    PubMed  CAS  Google Scholar 

  73. Kelleher, D. K., Thews, O. and Vaupel, P. (1999). Modulation of tumor oxygenation and radiosensitivity by erythropoietin, in Tumor Hypoxia (P. Vaupel and D. K. Kelleher, eds), pp 83–90, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  74. Lavey, R. S. (1999). Clinical trial experience using erythropoietin during radiation therapy. in Tumor Hypoxia (P. Vaupel and D. K. Kelleher, eds), pp 99–105, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  75. Teicher, B. A., Holden, S. A., Al-Achi, A. and Herman, T. S. (1990). Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSall murine fibrosarcoma. Cancer Res. 50:3339–3344.

    PubMed  CAS  Google Scholar 

  76. Walker, L. J., Craig, R. B., Harris, A. L. and Hickson, I. D. (1994). A role for the human DNA-repair enzyme HAP1 in cellular-protection against DNA-damaging agents and hypoxic stress. Nucleic Acids Res. 22:4884–4889.

    Article  PubMed  CAS  Google Scholar 

  77. Chabner, B., Allegra, C. J., Curt, G. A. and Calabresi, P. (1996). Antineoplastic agents, in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., pp 1233–1287, McGraw-Hill, New York.

    Google Scholar 

  78. Sakata, K., et al. (1991). Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br. J. Cancer 64:809–814.

    PubMed  CAS  Google Scholar 

  79. Hickman, J. A., Potten, C. S., Merritt, A. J. and Fisher, T. C. (1994). Apoptosis and cancer chemotherapy. Philos. Trans. R. Soc. B 345:319–325.

    Article  CAS  Google Scholar 

  80. Thews, O., Kelleher, D. K. and Vaupel, P. (2001). Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res. 61:1358–1361.

    PubMed  CAS  Google Scholar 

  81. Silver, D. F. and Piver, M. S. (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. 73:280–284.

    Article  PubMed  CAS  Google Scholar 

  82. Freitas, I. and Baronzio, G. F. (1991). Tumor hypoxia, reoxygenation and oxygenation strategies: possible role in photodynamic therapy. J. Photochem. Photobiol. B: Biol. 11:3–30.

    Article  CAS  Google Scholar 

  83. Henderson, B. W. and Fingar, V. H. (1987). Relationship of tumor hypoxia and response to photodynamic treatment in an experimental mouse tumor. Cancer Res. 47:3110–3114.

    PubMed  CAS  Google Scholar 

  84. Moan, J. and Sommer, S. (1985). Oxygen dependence of the photosensitizing effect of hematoporphyrin derivative in NHIK 3025 cells. Cancer Res. 45:1608–1610.

    PubMed  CAS  Google Scholar 

  85. Mitchell, J. B., et al. (1985). Oxygen dependence of hematoporphyrin derivative-induced photo-inactivation of Chinese hamster cells. Cancer Res. 45:2008–2011.

    PubMed  CAS  Google Scholar 

  86. Chapman, J. D., et al. (1991). Oxygen dependency of tumor cell killing in vitro by light-activated Photofrin II. Radiat. Res. 126:73–79.

    Article  PubMed  CAS  Google Scholar 

  87. Vaupel, P. and Hoeckel, M. (2002). Tumor hypoxia and therapeutic resistance, in Recombinant Human Erythropoietin (rhEPO) in Clincial Oncology (M. R. Nowrousian, ed), Springer-Verlag, Berlin, in press.

    Google Scholar 

  88. Semenza, G. L. (2000). Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol. 35:71–103.

    Article  PubMed  CAS  Google Scholar 

  89. Semenza, G. L. (2000). HIF-1: mediator of physiological and pathophysiological response to hypoxia. J. Appl. Physiol. 88:1474–1480.

    PubMed  CAS  Google Scholar 

  90. Dachs, G. U. and Tozer, G. M. (2000). Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur. J. Cancer 36:1649–1660.

    Article  PubMed  CAS  Google Scholar 

  91. Giaccia, A. J. (1996). Hypoxic stress proteins: survival of the fittest. Semin. Radiat. Oncol. 6:46–58.

    Article  PubMed  Google Scholar 

  92. Laderoute, K. R., Grant, T. D., Murphy, B. J. and Sutherland, R. M. (1992). Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen. Int. J. Cancer 52:428–432.

    Article  PubMed  CAS  Google Scholar 

  93. Sutherland, R. M. (1998). Tumor hypoxia and gene expression. Implications for malignant progression and therapy. Acta Oncol. 37:567–574.

    Article  PubMed  CAS  Google Scholar 

  94. Cheng, K. C. and Loeb, L. A. (1993). Genomic instability and tumor progression: mechanistic considerations. Adv. Cancer Res. 60:121–156.

    Article  PubMed  CAS  Google Scholar 

  95. De Jaeger, K., Kavanagh, M.-C. and Hill, R. P. (2001). Relationship of hypoxia to metastatic ability in rodent tumours. Br. J. Cancer 84:1280–1285.

    Article  PubMed  Google Scholar 

  96. Graeber, T. G., et al. (1996). Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91.

    Article  PubMed  CAS  Google Scholar 

  97. Kim, C. Y., et al. (1997). Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions. Cancer Res. 57:4200–4204.

    PubMed  CAS  Google Scholar 

  98. Reynolds, T. Y., Rockwell, S. and Glazer, P. M. (1996). Genetic instability induced by the tumor microenvironment. Cancer Res. 56:5754–5757.

    PubMed  CAS  Google Scholar 

  99. Rofstad, E. K. (2000). Microenvironment-induced cancer metastasis. Int. J. Radiat. Biol. 76:589–605.

    Article  PubMed  CAS  Google Scholar 

  100. Höckel, M., Schlenger K., Höckel, S. and Vaupel, P. (1999). Association between tumor hypoxia and malignant progression: the clinical evidence in cancer of the uterine cervix, in Tumor Hypoxia (P. Vaupel and D. K. Kelleher, eds), pp 65–74, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

    Google Scholar 

  101. Höckel, M. and Vaupel, P. (2001). Biological consequences of tumor hypoxia. Semin. Oncol. 28(Suppl. 8):36–41.

    Article  PubMed  Google Scholar 

  102. Rofstad, E. K. and Maseide, K. (1999). Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours. Int. J. Radiat. Biol. 75:1377–1393.

    Article  PubMed  CAS  Google Scholar 

  103. Thews, O., Kelleher, D. K. and Vaupel, P. (2001). Dynamics of tumor oxygenation and red blood cell flux in response to inspiratory hyperoxia combined with different levels of inspiratory hypercapnia. Radiother. Oncol. in press.

  104. Aebersold, D. M., et al. (2001). Expression of hypoxia-inducible factor-1α: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61:2911–2916.

    PubMed  CAS  Google Scholar 

  105. Ratcliffe, P. J., Pugh, C. W. and Maxwell, P. H. (2000). Targeting tumors through the HIF system. Nature Med. 6:1315–1316.

    Article  PubMed  CAS  Google Scholar 

  106. Kung, A. L., Wang, S., Klico, J. M., Kaelin, W. G. and Livingston, D. M. (2000). Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Med. 6:1335–1340.

    Article  PubMed  CAS  Google Scholar 

  107. Caro, J. J., Salas, M., Ward, A. and Goss, G. Anemia as an independent prognostic factor for survival in patients with cancer. Cancer 91: 2214–2221.

  108. Dunst, J. (2001). The use of epoietin alfa to increase and maintain hemoglobin levels during radiotherapy. Semin. Oncol. 28(Suppl. 8):42–48.

    Article  PubMed  CAS  Google Scholar 

  109. Littlewood, T. J. (2001). The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin. Oncol. 28(Suppl. 8):49–53.

    Article  PubMed  CAS  Google Scholar 

  110. Wagner, W., et al. (2000). Prognostic value of hemoglobin concentrations in patients with advanced head and neck cancer treated with combined radio-chemotherapy and surgery. Strahlenther. Onkol. 176:73–80.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics & Gynecology, University of Leipzig, 04103, Leipzig, Germany

    Michael Hoeckel

  2. Institute of Physiology & Pathophysiology, University of Mainz, Duesbergweg 6, 55099, Mainz, Germany

    Peter Vaupel & Oliver Thews

Authors
  1. Peter Vaupel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Thews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Hoeckel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Vaupel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaupel, P., Thews, O. & Hoeckel, M. Treatment resistance of solid tumors. Med Oncol 18, 243–259 (2001). https://doi.org/10.1385/MO:18:4:243

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MO:18:4:243

Key Words

Search

Navigation