Radiolabelled peptides for tumour therapy: current status and future directions

Plenary lecture at the EANM 2002
  • Marion de JongEmail author
  • Dik Kwekkeboom
  • Roelf Valkema
  • Eric P. Krenning
Review Article


On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, e.g. overexpression in many tumours, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualisation of receptor-positive tumours were radiolabelled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicentre studies have already shown an effective therapeutic response when using radiolabelled somatostatin analogues to treat receptor-positive tumours. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumours, such as medullary thyroid carcinoma, radiolabelled minigastrin analogues are currently being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabelled peptides. The combination of different radionuclides, such as 177Lu- and 90Y-labelled somatostatin analogues, to reach a wider tumour region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y1) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multi-receptor tumour targeting using the combination of bombesin and NPY(Y1) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases.


Peptides Radionuclide therapy Somatostatin Bombesin NPY 


  1. 1.
    Reubi JC, Krenning E, Lamberts SW, Kvols L. Somatostatin receptors in malignant tissues. J Steroid Biochem Mol Biol 1990; 37:1073–1077.Google Scholar
  2. 2.
    Reubi JC, Kvols L, Krenning E, Lamberts SW. In vitro and in vivo detection of somatostatin receptors in human malignant tissues. Acta Oncol 1991; 30:463–468.Google Scholar
  3. 3.
    Reubi JC, Laissue J, Krenning E, Lamberts SW. Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications. J Steroid Biochem Mol Biol 1992; 43:27–35.Google Scholar
  4. 4.
    Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20:716–731.Google Scholar
  5. 5.
    Krenning EP, Bakker WH, Breeman WA, Koper JW, Kooij PP, Ausema L, Lameris JS, Reubi JC, Lamberts SW. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1989; 1:242–244.Google Scholar
  6. 6.
    Krenning EP, Bakker WH, Kooij PP, et al. Somatostatin receptor scintigraphy with indium-111-DTPA-d-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med 1992; 33:652–658.Google Scholar
  7. 7.
    Goldsmith SJ, Kostakoglu L. Role of nuclear medicine in the evaluation of the solitary pulmonary nodule. Semin Ultrasound CT MR 2000; 21:129–138.Google Scholar
  8. 8.
    Blum J, Handmaker H, Lister-James J, Rinne N. A multicenter trial with a somatostatin analog (99m)Tc depreotide in the evaluation of solitary pulmonary nodules. Chest 2000; 117:1232–1238.Google Scholar
  9. 9.
    Behr TM, Behe MP. Cholecystokinin-B/gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. Semin Nucl Med 2002; 32:97–109.Google Scholar
  10. 10.
    Kwekkeboom DJ, Bakker WH, Kooij PP, Erion J, Srinivasan A, de Jong M, Reubi JC, Krenning EP. Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med 2000; 27:1312–1317.Google Scholar
  11. 11.
    van Hagen PM, Breeman WA, Reubi JC, Postema PT, van den Anker-Lugtenburg PJ, Kwekkeboom DJ, Laissue J, Waser B, Lamberts SW, Visser TJ, Krenning EP. Visualization of the thymus by substance P receptor scintigraphy in man. Eur J Nucl Med 1996; 23:1508–1513.Google Scholar
  12. 12.
    Behr TM, Jenner N, Radetzky S, Behe M, Gratz S, Yucekent S, Raue F, Becker W. Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin. Eur J Nucl Med 1998; 25:424–430.Google Scholar
  13. 13.
    Behr TM, Gotthardt M, Barth A, Behe M. Imaging tumors with peptide-based radioligands. Q J Nucl Med 2001; 45:189–200.Google Scholar
  14. 14.
    Behr TM, Behe M, Angerstein C, Gratz S, Mach R, Hagemann L, Jenner N, Stiehler M, Frank-Raue K, Raue F, Becker W. Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential. Clin Cancer Res 1999; 5(10 Suppl):3124s–3138s.Google Scholar
  15. 15.
    Reubi C, Gugger M, Waser B. Co-expressed peptide receptors in breast cancer as a molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 2002; 29:855–862.Google Scholar
  16. 16.
    Reubi JC, Gugger M, Waser B, Schaer JC. Y(1)-mediated effect of neuropeptide Y in cancer: breast carcinomas as targets. Cancer Res 2001; 61:4636–4641.Google Scholar
  17. 17.
    Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res 1997; 57:1377–1386.Google Scholar
  18. 18.
    Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res 2000; 60:3105–3112.Google Scholar
  19. 19.
    Virgolini I, Kurtaran A, Raderer M, et al. Vasoactive intestinal peptide receptor scintigraphy. J Nucl Med 1995; 36:1732–1739.Google Scholar
  20. 20.
    Virgolini I, Raderer M, Kurtaran A, Angelberger P, Yang Q, Radosavljevic M, Leimer M, Kaserer K, Li SR, Kornek G, Hubsch P, Niederle B, Pidlich J, Scheithauer W, Valent P.123I-vasoactive intestinal peptide (VIP) receptor scanning: update of imaging results in patients with adenocarcinomas and endocrine tumors of the gastrointestinal tract. Nucl Med Biol 1996; 23:685–692.Google Scholar
  21. 21.
    Virgolini I, Szilvasi I, Kurtaran A, Angelberger P, Raderer M, Havlik E, Vorbeck F, Bischof C, Leimer M, Dorner G, Kletter K, Niederle B, Scheithauer W, Smith-Jones P. Indium-111-DOTA-lanreotide: biodistribution, safety and radiation absorbed dose in tumor patients. J Nucl Med 1998; 39:1928–1936.Google Scholar
  22. 22.
    Weiner RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases. Appl Radiat Isot 2002; 57:749–763.Google Scholar
  23. 23.
    Krenning EP, Kwekkeboom DJ, Oei HY, de Jong RJ, Dop FJ, Reubi JC, Lamberts SW. Somatostatin-receptor scintigraphy in gastroenteropancreatic tumors. An overview of European results. Ann N Y Acad Sci 1994; 733:416–424.Google Scholar
  24. 24.
    Kwekkeboom D, Krenning EP, de Jong M. Peptide receptor imaging and therapy. J Nucl Med 2000; 41:1704–1713.Google Scholar
  25. 25.
    Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, Macke HR. Affinity profiles for human somatostatin receptor subtypes SST1–SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000; 27:273–282.Google Scholar
  26. 26.
    Valkema R, De Jong M, Bakker WH, Breeman WA, Kooij PP, Lugtenburg PJ, De Jong FH, Christiansen A, Kam BL, De Herder WW, Stridsberg M, Lindemans J, Ensing G, Krenning EP. Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience. Semin Nucl Med 2002; 32:110–122.Google Scholar
  27. 27.
    McCarthy KE, Woltering EA, Anthony LB. In situ radiotherapy with111In-pentetreotide. State of the art and perspectives. Q J Nucl Med 2000; 44:88–95.Google Scholar
  28. 28.
    Anthony LB, Woltering EA, Espenan GD, Cronin MD, Maloney TJ, McCarthy KE. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med 2002; 32:123–132.Google Scholar
  29. 29.
    de Jong M, Breeman WA, Bakker WH, Kooij PP, Bernard BF, Hofland LJ, Visser TJ, Srinivasan A, Schmidt MA, Erion JL, Bugaj JE, Macke HR, Krenning EP. Comparison of (111)In-labeled somatostatin analogues for tumor scintigraphy and radionuclide therapy. Cancer Res 1998; 58:437–441.Google Scholar
  30. 30.
    De Jong M, Bakker WH, Breeman WA, Bernard BF, Hofland LJ, Visser TJ, Srinivasan A, Schmidt M, Behe M, Macke HR, Krenning EP. Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Int J Cancer 1998; 75:406–411.Google Scholar
  31. 31.
    De Jong M, Breeman WAP, Bernard HF, Bakker WH, Van Gameren A, Bugaj JE, Erion J, Srinivasan A, Maecke HR, Krenning EP. Receptor-targeted radionuclide therapy using radiolabelled somatostatin analogues: tumour size versus curability. Eur J Nucl Med 2001; 28:1026P.Google Scholar
  32. 32.
    de Jong M, Breeman WA, Bernard BF, Bakker WH, Visser TJ, Kooij PP, van Gameren A, Krenning EP. Tumor Response After [(90)Y-DOTA(0),Tyr(3)]octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size. J Nucl Med 2001; 42:1841–1846.Google Scholar
  33. 33.
    Virgolini I, Patri P, Novotny C, Traub T, Leimer M, Fuger B, Li SR, Angelberger P, Raderer M, Wogritsch S, Kurtaran A, Kletter K, Dudczak R. Comparative somatostatin receptor scintigraphy using In-111-DOTA-lanreotide and In-111-DOTA-Tyr3-octreotide versus F-18-FDG-PET for evaluation of somatostatin receptor-mediated radionuclide therapy. Ann Oncol 2001; 12 (Suppl 2):S41–S45.Google Scholar
  34. 34.
    Heppeler A, Froidevaux S, Mäcke HR, Jermann E, Béhé M, Powell P, Hennig M. Radiometal-labelled macrocyclic chelator-derivatised somatostatin analogue with superb tumour-targeting properties and potential for receptor-mediated internal radiotherapy. Chem Eur J 1999; 5:1974–1981.Google Scholar
  35. 35.
    Kwekkeboom DJ, Kooij PP, Bakker WH, Macke HR, Krenning EP. Comparison of111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake. J Nucl Med 1999; 40:762–767.Google Scholar
  36. 36.
    Chinol M, Bodei L, Cremonesi M, Paganelli G. Receptor-mediated radiotherapy with Y-DOTA-dPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group. Semin Nucl Med 2002; 32:141–147.Google Scholar
  37. 37.
    Paganelli G, Zoboli S, Cremonesi M, Bodei L, Ferrari M, Grana C, Bartolomei M, Orsi F, De Cicco C, Macke HR, Chinol M, de Braud F. Receptor-mediated radiotherapy with90Y-DOTA-d-Phe1-Tyr3-octreotide. Eur J Nucl Med 2001; 28:426–434.Google Scholar
  38. 38.
    Paganelli G, Bodei L, Chinol M, Zoboli S, Cremonesi M, Gatti M, Bartolomei M, Grana C, Maecke H. Receptor mediated radiotherapy with90Y-DOTATOC: results of a phase I study. J Nucl Med 2001; 42:36P.Google Scholar
  39. 39.
    Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-d-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol 2001; 12:941–945.Google Scholar
  40. 40.
    Waldherr C, Pless M, Maecke HR, Schumacher T, Crazzolara A, Nitzsche EU, Haldemann A, Mueller-Brand J. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq90Y-DOTATOC. J Nucl Med 2002; 43:610–616.Google Scholar
  41. 41.
    Waldherr C, Schumacher T, Maecke HR, Schirp U, Forrer F, Nitzsche EU, Mueller-Brand J. Does tumor response depend on the number of treatment sessions at constant injected dose using 90yttrium-DOTATOC in neuroendocrine tumors? Eur J Nucl Med 2002; 29:S100.Google Scholar
  42. 42.
    De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA, Bakker WH, Smith C, Pauwels S, Krenning EP. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med 2002; 32:133–140.Google Scholar
  43. 43.
    Smith MC, Liu J, Chen T, Schran H, Yeh CM, Jamar F, Valkema R, Bakker W, Kvols L, Krenning E, Pauwels S. OctreoTher: ongoing early clinical development of a somatostatin- receptor-targeted radionuclide antineoplastic therapy. Digestion 2000; 62 (Suppl 1):69–72.Google Scholar
  44. 44.
    Valkema R, Kvols L, Jamar F, Bakker WH, Smith C, Krenning EP, Pauwels S. Phase 1 study of therapy with90Y-SMT487 (OctreoTher) in patients with somatostatin receptor-positive tumors. J Nucl Med 2002; 43:33P.Google Scholar
  45. 45.
    Jonard P, Jamar F, Walrand S, Collart JP, Valkema R, Bakker WH, Labar D, Smith C, Kvols L, Krenning EP, Pauwels S. Tumor dosimetry based on PET86Y-DOTA-Tyr3-octreotide (SMT487) and CT-scan predicts tumor response to 90Y-SMT487 (OctreoTher). J Nucl Med 2000; 41:111P.Google Scholar
  46. 46.
    Schumacher T, Hofer S, Eichhorn K, Wasner M, Zimmerer S, Freitag P, Probst A, Gratzl O, Reubi JC, Maecke R, Mueller-Brand J, Merlo A. Local injection of the90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study. Eur J Nucl Med Mol Imaging 2002; 29:486–493.Google Scholar
  47. 47.
    Virgolini I, Britton K, Buscombe J, Moncayo R, Paganelli G, Riva P. In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin Nucl Med 2002; 32:148–155.Google Scholar
  48. 48.
    Virgolini I, Kurtaran A, Angelberger P, Raderer M, Havlik E, Smith-Jones P. "MAURITIUS": tumour dose in patients with advanced carcinoma. Ital J Gastroenterol Hepatol 1999; 31 (Suppl 2):S227–S230.Google Scholar
  49. 49.
    Virgolini I, Traub T, Novotny C, Leimer M, Fuger B, Li SR, Patri P, Pangerl T, Angelberger P, Raderer M, Burggasser G, Andreae F, Kurtaran A, Dudczak R. Experience with indium-111 and yttrium-90-labeled somatostatin analogs. Curr Pharm Des 2002; 8:1781–1807.Google Scholar
  50. 50.
    Kwekkeboom DJ, Bakker WH, Kooij PPM, Konijnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JE, de Jong M, Krenning EP. [177Lu-DOTA0,Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients. Eur J Nucl Med 2001; 28:1319–1325.Google Scholar
  51. 51.
    de Jong M, Breeman WA, Bernard BF, Bakker WH, Schaar M, van Gameren A, Bugaj JE, Erion J, Schmidt M, Srinivasan A, Krenning EP. [177Lu-DOTA(0),Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int J Cancer 2001; 92:628–633.Google Scholar
  52. 52.
    Kwekkeboom DJ, Bakker WH, Kam BL, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med (in press). DOI 10.1007/s00259-002-1050-8.Google Scholar
  53. 53.
    Cybulla M, Weiner SM, Otte A. End-stage renal disease after treatment with90Y-DOTATOC. Eur J Nucl Med 2001; 28:1552–1554.Google Scholar
  54. 54.
    Behr TM, Behe M, Kluge G, Gotthardt M, Schipper ML, Gratz S, Arnold R, Becker W, Goldenberg DM. Nephrotoxicity versus anti-tumour efficacy in radiopeptide therapy: facts and myths about the Scylla and Charybdis. Eur J Nucl Med Mol Imaging 2002; 29:277–279.Google Scholar
  55. 55.
    Boerman OC, Oyen WJ, Corstens FH. Between the Scylla and Charybdis of peptide radionuclide therapy: hitting the tumor and saving the kidney. Eur J Nucl Med 2001; 28:1447–1449.Google Scholar
  56. 56.
    Valkema R, de Jong M, Kooij PPM, Kwekkeboom D, Krenning EP. Effective and safe inhibition of renal uptake of radiolabeled peptides by combined lysine and arginine infusion. J Nucl Med 2001; 42:37P.Google Scholar
  57. 57.
    Rolleman EJ, Valkema R, de Jong M, Kooij PPM, Krenning EP. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur J Nucl Med Mol Imaging 2003; 30:9–15.Google Scholar
  58. 58.
    Reubi JC, Waser B, Laderach U, Stettler C, Friess H, Halter F, Schmassmann A. Localization of cholecystokinin A and cholecystokinin B-gastrin receptors in the human stomach. Gastroenterology 1997; 112:1197–1205.Google Scholar
  59. 59.
    de Jong M, Bakker WH, Bernard BF, Valkema R, Kwekkeboom DJ, Reubi JC, Srinivasan A, Schmidt M, Krenning EP. Preclinical and initial clinical evaluation of111In-labeled nonsulfated CCK8 analog: a peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy. J Nucl Med 1999; 40:2081–2087.Google Scholar
  60. 60.
    Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer JC, Gugger M. Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[d-Tyr(6), beta-Ala(11), Phe(13), NLE(14)] bombesin(6-14). Clin Cancer Res 2002; 8:1139–1146.Google Scholar
  61. 61.
    Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res 1999; 59:1152–1159.Google Scholar
  62. 62.
    Schmitt JS, Wild D, Ginj M, Reubi JC, Waser B, De Jong M, Bernard HF, Krenning EP, Maecke HR. DOTA-NOC, a high affinity ligand of the somatostatin receptor subtypes 2,3 and 5 for radiotherapy. J Labelled Cpd Radiopharm 2001; 44:s697–s699.Google Scholar
  63. 63.
    O'Donoghue JA, Bardies M, Wheldon TE. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides [see comments]. J Nucl Med 1995; 36:1902–1909.Google Scholar
  64. 64.
    De Jong M, Bernard HF, Breeman WAP, van Gameren A, Krenning EP. Combination of90Y- and 177Lu-labeled somatostatin analogs is superior for radionuclide therapy compared to 90Y- or 177Lu-labeled analogs only. J Nucl Med 2002; 43:123P–124P.Google Scholar
  65. 65.
    Gugger M, Reubi JC. Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am J Pathol 1999; 155:2067–2076.Google Scholar
  66. 66.
    De Vincentis G, Scopinaro F, Varvarigou A, Ussof W, Schillaci O, Archimandritis , Corleto V, Longo F, Delle Fave G. Phase I trial of technetium [Leu13] bombesin as cancer seeking agent: possible scintigraphic guide for surgery? Tumori 2002; 88:S28–S30.Google Scholar
  67. 67.
    Scopinaro F, Varvarigou A, Ussof W, De Vincentis G, Archimandritis S, Evangelatos G, Corleto V, Pulcini A, Capoccetti F, Remediani S, Massa R. Breast cancer takes up99mTc bombesin. A preliminary report. Tumori 2002; 88:S25–S28.Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Marion de Jong
    • 1
    Email author
  • Dik Kwekkeboom
    • 1
  • Roelf Valkema
    • 1
  • Eric P. Krenning
    • 1
  1. 1.Department of Nuclear Medicine, L2Erasmus MCRotterdamThe Netherlands

Personalised recommendations