Skip to main content

Advertisement

SpringerLink
Log in

Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211At-EGF

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

The EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) gefitinib ['Iressa' (trademark of the AstraZeneca group of companies), ZD1839] increases the cellular uptake of radiolabelled epidermal growth factor (EGF). We investigated gefitinib treatment combined with astatine-211 EGF targeting in vitro using two cell lines expressing high levels of EGFR: A431 (sensitive to gefitinib) and U343MGaCl2:1 (resistant to gefitinib). In both cell lines, the uptake of 211At-EGF was markedly increased by concomitant treatment with gefitinib. Survival was investigated using both a clonogenic survival assay and a cell growth assay. Combined gefitinib and 211At-EGF treatment reduced the survival of U343 cells 3.5-fold compared with 211At-EGF alone. In A431 cells, 211At-EGF treatment resulted in very low survival, but combined treatment with gefitinib increased the survival by about 20-fold. These results indicate that combined treatment with gefitinib might increase the effect of ligand-mediated radionuclide therapy in gefitinib-resistant tumours and decrease the effect of such therapy in gefitinib-sensitive tumours.

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.

Fig. 1a, b.
Fig. 2a, b.
Fig. 3a, b.
Fig. 4a, b.
Fig. 5a, b.
Fig. 6a–d.

Similar content being viewed by others

References

  1. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183–232.

    Article  CAS  PubMed  Google Scholar 

  2. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem 1990; 265:7709–7712.

    CAS  PubMed  Google Scholar 

  3. Sorkin A. Endocytosis and intracellular sorting of receptor tyrosine kinases. Front Biosci 1998; 3:D729–D738.

    CAS  PubMed  Google Scholar 

  4. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127–137.

    Article  CAS  PubMed  Google Scholar 

  5. Bigner SH, Burger PC, Wong AJ, Werner MH, Hamilton SR, Muhlbaier LH, Vogelstein B, Bigner DD. Gene amplification in malignant human gliomas: clinical and histopathologic aspects. J Neuropathol Exp Neurol 1988; 47:191–205.

    CAS  PubMed  Google Scholar 

  6. Collins VP. Amplified genes in human gliomas. Semin Cancer Biol 1993; 4:27–32.

    CAS  PubMed  Google Scholar 

  7. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002; 7 Suppl 4:2–8.

    Google Scholar 

  8. Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, Dyson NJ. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res 2001; 7:2387–2395.

    CAS  PubMed  Google Scholar 

  9. Kim H, Muller WJ. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res 1999; 253:78–87.

    Article  CAS  PubMed  Google Scholar 

  10. Laird AD, Cherrington JM. Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs 2003; 12:51–64.

    CAS  PubMed  Google Scholar 

  11. Normanno N, Maiello MR, De Luca A. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): simple drugs with a complex mechanism of action? J Cell Physiol 2003; 194:13–19.

    Article  CAS  PubMed  Google Scholar 

  12. Denny WA. The 4-anilinoquinazoline class of inhibitors of the erbB family of receptor tyrosine kinases. Farmaco 2001; 56:51–56.

    Article  CAS  PubMed  Google Scholar 

  13. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, Averbuch SD, Feyereislova A, Swaisland H, Rojo F, Albanell J. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002; 20:4292–4302.

    Article  CAS  PubMed  Google Scholar 

  14. Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62:5749–5754.

    CAS  PubMed  Google Scholar 

  15. Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61:8887–8895.

    CAS  PubMed  Google Scholar 

  16. Normanno N, Campiglio M, De LA, Somenzi G, Maiello M, Ciardiello F, Gianni L, Salomon DS, Menard S. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002; 13:65–72.

    Article  CAS  PubMed  Google Scholar 

  17. Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6:2053–2063.

    CAS  PubMed  Google Scholar 

  18. Bianco C, Tortora G, Bianco R, Caputo R, Veneziani BM, Caputo R, Damiano V, Troiani T, Fontanini G, Raben D, Pepe S, Bianco AR, Ciardiello F. 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 2002; 8:3250–3258.

    CAS  PubMed  Google Scholar 

  19. Huang SM, Li J, Armstrong EA, Harari PM. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 2002; 62:4300–4306.

    CAS  PubMed  Google Scholar 

  20. Solomon B, Hagekyriakou J, Trivett MK, Stacker SA, McArthur GA, Cullinane C. EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2003; 55:713–723.

    Article  CAS  PubMed  Google Scholar 

  21. Williams KJ, Telfer BA, Stratford IJ, Wedge SR. ZD1839 ('Iressa'), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model. Br J Cancer 2002; 86:1157–1161.

    Article  CAS  PubMed  Google Scholar 

  22. Lichtner RB, Menrad A, Sommer A, Klar U, Schneider MR. Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors. Cancer Res 2001; 61:5790–5795.

    CAS  PubMed  Google Scholar 

  23. Sundberg AL, Almqvist Y, Tolmachev V, Carlsson J. Treatment of cultured glioma cells with the EGFR-TKI gefitinib ("Iressa", ZD1839) increases the uptake of astatinated EGF despite the absence of gefitinib-mediated growth inhibition. Eur J Nucl Med Mol Imaging 2003; 30:727–729.

    CAS  PubMed  Google Scholar 

  24. Zalutsky MR, Vaidyanathan G. Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy. Curr Pharm Des 2000; 6:1433–1455.

    CAS  PubMed  Google Scholar 

  25. Barker FG 2, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK, Wara WM, Berger MS, Chen P, Israel MA, Aldape KD. EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2001; 51:410–418.

    Google Scholar 

  26. Chaffanet M, Chauvin C, Laine M, Berger F, Chedin M, Rost N, Nissou MF, Benabid AL. EGF receptor amplification and expression in human brain tumours. Eur J Cancer 1992; 28:11–17.

    CAS  PubMed  Google Scholar 

  27. Lang O, Liebermeister E, Liesegang J, Sautter-Bihl ML. Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment. Strahlenther Onkol 1998; 174:629–632.

    CAS  PubMed  Google Scholar 

  28. Nieder C, Nestle U, Ketter R, Kolles H, Gentner SJ, Steudel WI, Schnabel K. Hyperfractionated and accelerated-hyperfractionated radiotherapy for glioblastoma multiforme. Radiat Oncol Investig 1999; 7:36–41.

    Article  CAS  PubMed  Google Scholar 

  29. Boiardi A, Silvani A, Pozzi A, Fariselli L, Broggi G, Salmaggi A. Interstitial chemotherapy plus systemic chemotherapy for glioblastoma patients: improved survival in sequential studies. J Neurooncol 1999; 41:151–157.

    Article  CAS  PubMed  Google Scholar 

  30. Benveniste R, Danoff TM, Ilekis J, Craig HR. Epidermal growth factor receptor numbers in male and female mouse primary hepatocyte cultures. Cell Biochem Funct 1988; 6:231–235.

    CAS  PubMed  Google Scholar 

  31. Kiss A, Schnur J, Szabó Z, Nagy P. Immunohistochemical analysis of atypical ductular reaction in the human liver, with special emphasis on the presence of growth factors and their receptors. Liver 2001; 21:237–246.

    Article  CAS  PubMed  Google Scholar 

  32. Yang W, Barth RF, Leveille R, Adams DM, Ciesielski M, Fenstermaker RA, Capala J. Evaluation of systemically administered radiolabeled epidermal growth factor as a brain tumor targeting agent. J Neurooncol 2001; 55:19–28.

    Article  CAS  PubMed  Google Scholar 

  33. Heimberger AB, Learn CA, Archer GE, McLendon RE, Chewning TA, Tuck KL, Pracyk JB, Friedman AH, Friedman HS, Bigner DD, Sampson JH. Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 2002; 8:3496–3502.

    CAS  PubMed  Google Scholar 

  34. Capala J, Prahl M, Scott-Robson S, Ponten J, Westermark B, Carlsson J. Effects of131I-EGF on cultured human glioma cells. J Neurooncol 1990; 9:201–210.

    CAS  PubMed  Google Scholar 

  35. Gilmore AP, Valentijn AJ, Wang P, Ranger AM, Bundred N, O'Hare MJ, Wakeling A, Korsmeyer SJ, Streuli CH. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 2002; 277:27643–27650.

    Article  CAS  PubMed  Google Scholar 

  36. Sartor CI. Epidermal growth factor family receptors and inhibitors: radiation response modulators. Semin Radiat Oncol 2003; 13:22–30.

    Article  PubMed  Google Scholar 

  37. Hartman T, Lundqvist H, Westlin JE, Carlsson J. Radiation doses to the cell nucleus in single cells and cells in micrometastases in targeted therapy with (131)I labeled ligands or antibodies. Int J Radiat Oncol Biol Phys 2000; 46:1025–1036.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Professor Hans Lundquist and Ass. Professor Bo Stenerlöw for valuable discussions on radiophysics and radiobiology. Gefitinib was kindly provided by AstraZeneca, Macclesfield, UK. Financial support was given by the Swedish Cancer Society, 0980-B02-15XAC [J.C.]. We are also grateful for financial contributions from Lions Cancer Fund at Akademiska Sjukhuset, Uppsala.

Author information

Authors and Affiliations

  1. Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden

    Åsa Liljegren Sundberg, Anna Orlova, Lars Gedda, Vladimir Tolmachev & Jörgen Carlsson

  2. Division of Radiology, Uppsala University, Uppsala, Sweden

    Ylva Almqvist

  3. Division of Oncology, Uppsala University, Uppsala, Sweden

    Erik Blomquist

  4. Department of Clinical Physiology and Nuclear Medicine, PET and Cyclotron Unit , Rigshospitalet, Copenhagen, Denmark

    Holger J. Jensen

Authors
  1. Åsa Liljegren Sundberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ylva Almqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Orlova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erik Blomquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Holger J. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars Gedda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vladimir Tolmachev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jörgen Carlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Åsa Liljegren Sundberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sundberg, Å.L., Almqvist, Y., Orlova, A. et al. Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211At-EGF. Eur J Nucl Med Mol Imaging 30, 1348–1356 (2003). https://doi.org/10.1007/s00259-003-1308-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-003-1308-9

Keywords

Search

Navigation