Tumor Reoxygenation Following Administration of the EGFR Inhibitor, Gefitinib, in Experimental Tumors

  • Oussama Karroum
  • Julie Kengen
  • Vincent Grégoire
  • Bernard Gallez
  • Bénédicte F. Jordan
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 789)


It is well recognized that tumor hypoxia is a critical determinant for response to therapy. The effect of an EGFR inhibitor/gefitinib (Iressa®) on tumor oxygenation was monitored daily using in vivo EPR (electron paramagnetic resonance) oximetry on TLT and FSaII tumor models. An increase in pO2 was shown at a dose of 45 mg/kg i.p. (n = 4/group/tumor model). This allowed the identification of a window of reoxygenation in both tumor models (with a maximum between 15 and 20 mmHg after 2 days of treatment). The increase in tumor oxygenation was shown to be the result of a decrease in oxygen consumption. This is the first report on the effect of gefitinib on oxygen consumption by tumor cells and subsequent increase in tumor oxygenation in vivo.


Electron Paramagnetic Resonance Oxygen Consumption Oxygen Consumption Rate Tumor Oxygenation Small Animal Positron Emission Tomography 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by grants from the Belgian National Fund for Scientific Research (FNRS), the Fonds Joseph Maisin, the Saint-Luc Foundation, the “Actions de Recherches Concertées-Communauté Française de Belgique-ARC 09/14-020,” and the “ Pôle d’Attraction Interuniversitaire PAI VI (P6/38).” OK is “Televie” researcher, and BFJ is Research Associate of the Belgian National Fund for Scientific Research (FNRS).


  1. 1.
    Leo C, Giaccia AJ, Denko NC (2004) The hypoxic tumor microenvironment and gene expression. Semin Radiat Oncol 14(3):207–214CrossRefPubMedGoogle Scholar
  2. 2.
    Vaupel P, Kelleher DK, Thews O (1998) Modulation of tumor oxygenation. Int J Radiat Oncol Biol Phys 42(4):843–848CrossRefPubMedGoogle Scholar
  3. 3.
    Gray L, Conger A, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at time of irradiation as a factor in radiotherapy. Br J Radiol 26(312):638–648CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Horsman MR, van der Kogel AJ (2009) Therapeutic approaches to tumor hypoxia. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology, 4th edn. A Hodder Arnold Pub, London, pp 233–245CrossRefGoogle Scholar
  5. 5.
    Toustrup K, Sørensen BS, Lassen P et al (2012) Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 102(1):122–129CrossRefPubMedGoogle Scholar
  6. 6.
    Solomon B, Binns D, Roselt P et al (2005) Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging. Mol Cancer Ther 4(9):1417–1422CrossRefPubMedGoogle Scholar
  7. 7.
    Bianco C, Tortora G, Bianco R et al (2002) Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8(10):3250–3258PubMedGoogle Scholar
  8. 8.
    Wakeling AE, Guy SP, Woodburn JR et al (2002) ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62(20):5749–5754PubMedGoogle Scholar
  9. 9.
    Taper HS, Woolley GW, Teller MN, Lardis MP (1966) A new transplantable mouse liver tumor of spontaneous origin. Cancer Res 26:143–148PubMedGoogle Scholar
  10. 10.
    Volpe JP, Hunter N, Basic I, Milas L (1985) Metastatic properties of murine sarcomas and carcinomas. I. Positive correlation with lung colonization and lack of correlation with s.c. tumor take. Clin Exp Metastasis 3(4):281–294CrossRefGoogle Scholar
  11. 11.
    Gallez B, Baudelet C, Jordan BF (2004) Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 17(5):240–262CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gallez B, Jordan BF, Baudelet C, Misson PD (1999) Pharmacological modifications of the partial pressure of oxygen in murine tumors: evaluation using in vivo EPR oximetry. Magn Reson Med 42(4):627–630CrossRefGoogle Scholar
  13. 13.
    Sersa G, Cemazar M, Miklavcic D, Chaplin DJ (1999) Tumor blood flow modifying effect of electrochemotherapy with bleomycin. Anticancer Res 19(5B):4017–4022PubMedGoogle Scholar
  14. 14.
    James PE, Jackson SK, Grinberg OY, Schwartz HM (1995) The effects of endotoxin on oxygen consumption of various cell types in vitro: an EPR oximetry study. Free Radic Biol Med 18(4):641–647CrossRefPubMedGoogle Scholar
  15. 15.
    Secomb TW, Hsu R, Ong ET et al (1995) Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol 34(3):313–316CrossRefPubMedGoogle Scholar
  16. 16.
    Jordan BF, Gregoire V, Demeure RJ et al (2002) Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res 62(12):3555–3561PubMedGoogle Scholar
  17. 17.
    Jordan BF, Christian N, Crokart N, Grégoire V, Feron O, Gallez B (2007) Thyroid status is a key modulator of tumor oxygenation: implication for radiation therapy. Radiat Res 168(4):428–432CrossRefPubMedGoogle Scholar
  18. 18.
    Jordan BF, Gallez B (2010) Surrogate MR markers of response to chemo- or radiotherapy in association with co-treatments: a retrospective analysis of multi-modal studies. Contrast Media Mol Imaging 5(6):323–332CrossRefPubMedGoogle Scholar
  19. 19.
    Carloni S, Fabbri F, Brigliadori G et al (2010) Tyrosine kinase inhibitors gefitinib, lapatinib and sorafenib induce rapid functional alterations in breast cancer cells. Curr Cancer Drug Targets 10(4):422–431CrossRefPubMedGoogle Scholar
  20. 20.
    Karroum O, Kengen J, Danhier P et al (2012) Tumor reoxygenation following administration of Mitogen-Activated Protein Kinase inhibitors: a rationale for combination with radiation therapy. Radiother Oncol 105(1):64–71CrossRefGoogle Scholar
  21. 21.
    Kang KB, Zhu C, Wong YL, Gao Q, Ty A, Wong MC (2012) Gefitinib radiosensitizes stem- like glioma cells: inhibition of epidermal growth factor receptor-Akt-DNA-PK signaling, accompanied by inhibition of DNA double-strand break repair. Int J Radiat Oncol Biol Phys 83(1):43–52CrossRefGoogle Scholar
  22. 22.
    Jordan BF, Sonveaux P (2012) Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy. Front Pharmacol 3:94CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Oussama Karroum
    • 1
  • Julie Kengen
    • 1
  • Vincent Grégoire
    • 2
  • Bernard Gallez
    • 1
  • Bénédicte F. Jordan
    • 1
  1. 1.Biomedical Magnetic Resonance Group, Louvain Drug Research InstituteUniversité catholique de LouvainBrusselsBelgium
  2. 2.Pole of Molecular Imaging, Radiotherapy and OncologyUniversité catholique de LouvainBrusselsBelgium

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