Nuklearmedizinische Diagnostik und Therapie neuroendokriner Tumoren des Gastrointestinaltraktes einschließlich des Karzinoides

Zusammenfassung

Neuroendokrine Tumoren des Gastrointestinaltrakts sind insbesondere seit der Entdeckung, dass diese Rezeptoren für regulatorische Peptide zuverlässig überexprimieren, die Domäne nuklearmedizinischer Diagnostik, in jüngerer Zeit auch nuklearmedizinischer Therapie geworden. Regulatorische Peptide sind kleine, leicht diffundierende, potente natürliche Substanzen mit einem weiten Spektrum rezeptorvermittelter Wirkungen. Hochaffine Rezeptoren für diese Peptide werden auf vielen Tumoren (über-)exprimiert, und diese Rezeptoren stellen neue molekulare Ziele zur Tumordiagnostik und -therapie dar. Während die historisch ältere MIBG-Szintigraphie nur begrenzte Sensitivität (bzw. in therapeutischer Applikation begrenzte Effektivität) gezeigt hat, hat die Somatostatin-Rezeptorszintigraphie das Staging (bzw. die Therapie) neuroendokriner gastroenteropankreatischer Tumoren revolutioniert. Physiologischerweise binden diese Peptide an G-Protein assoziierte Rezeptoren in der Zellmembran. Historisch gesehen sind die Somatostatin-Analoga die erste Klasse rezeptorbindender Peptide mit weiter klinischer Anwendung. ¹¹¹Indium-DTPA-[D-Phe¹]-Octreotid ist das erste und einzige Radiopeptid, das bislang in Europa und den Vereinigten Staaten Zulassung durch die entsprechenden Arzneimittelbehörden bekommen hat. Extensive klinische Studien mit vielen tausend Patienten konnten zeigen, dass die Hauptanwendung der Somatostatin- Rezeptorszintigraphie in der Detektion und im Staging gastroenteropankreatischer neuroendokriner Tumoren (Karzinoide u. a.) liegt. Bei diesen Tumoren ist die Octreotid- Szintigraphie jeder anderen Staging-Methode überlegen. Eine Vielzahl neuer radioaktiv markierter regulatorischer Peptide ist in Entwicklung, die an andere, neue Rezeptortypen binden. Radioaktiv markiertes vasoaktives intestinales Peptid (VIP), Gastrin- und Cholecystokinin-Derivate, Gastrin-releasing-peptide/Bombesin, Neurotensin, Substanz P, Glucagon-like peptide-1 (GLP-1)- Analoga und neuerdings auch an-Somatostatin-Rezeptorliganden stehen in unterschiedlich fortgeschrittenen Phasen der präklinischen und teilweise bereits klinischen Entwicklung. Radioaktiv markierte regulatorische Peptide haben neue Horizonte in der Nuklearonkologie zur Diagnostik und möglicherweise auch Therapie eröffnet.

Abstract

Neuroendocrine tumors of the gastrointestinal tract are the special domain of Nuclear Medical diagnosis and therapy, especially since they have been recognized as overexpressing receptors for regulatory peptides. Regulatory peptides are small, readily diffusible and potent natural substances with a wide spectrum of receptor-mediated actions. High affinity receptors are reliably (over-) expressed on a variety of tumors, and these receptors represent novel molecular targets for tumor diagnosis and therapy. Whereas the historically more ancient MIBG scintigraphy showed only limited sensitivity and therapeutic efficacy, somatostatin receptor scintigraphy has revolutionized the staging of gastroenteropancreatic tumors. Physiologically, these peptides bind to’G-protein associated receptors in the cell membranes. Historically, somatostatin analogues are the first class of receptor-binding peptides with a broader field of clinical applications. In-111-DTPA-[D- Phe1]-octreotide is the first and only radiopeptide having gained approval by the respective regulatory agencies in Europe and the United States of America. Extensive clinical studies with several thousands of patients were able to show that the main application of somatostatin receptor scintigraphy lies in the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids and others). In these, radiolabeled octreotide is superior to all other forms or methods of staging. A variety of novel radiolabeled regulatory peptides is in development, binding to other, novel receptor types. Radiolabeled vasoactive intestinal peptide (VIP), gastrin and cholecystokinin derivatives, gastrin-releasing peptide/bombesin, neurotensin, substance P, glucagon-like peptide-1 (GLP-1) analogues and potentially also pan-somatostatin receptor ligands stay in differently developed stages of their pre-clinical or even clinical testing. Radiolalebeled regulatory peptides have opened new horizons in Nuclear oncology for diagnosis and potential therapy.

Neuroendokrine Tumoren - Karzinoide - regulatorische Peptid(hormon)e - Peptidhormonrezeptoren - Somatostatin - Gastrin - Radioligandtherapie

Neuroendocrine tumors - carcinoids - regulatory peptide(hormone)s - peptide (hormone) receptors - somatostatin - gastrin - radioligand therapy

Literatur

• 1 Reubi J C, Landolt A M. High density of somatostatin receptors in pituitary tumors from acromegalic patients.  J Clin Endocrinol Metab. 1984;  59 1148-1151
• 2 Lamberts S W, Koper J W, Reubi J C. Potential role of somatostatin analogues in the treatment of cancer.  Eur J Clin Invest. 1987;  17 281-287
• 3 Reubi J C. Regulatory peptide receptors as molecular targets for cancer dioagnosis and therapy.  Q J Nucl Med. 1997;  41 63-70
• 4 Reubi J C. Neuropeptide receptors in health and disease: The molecular basis for in vivo imaging.  J Nucl Med. 1995;  36 1825-1835
• 5 Behr T M, Gotthardt M, Barth A, Béh é M. Imaging tumors with peptide-based radioligands.  Q J Nucl Med. 2001;  45 189-200
• 6 Behr T M, Jenner N, Béhé M, Angerstein C, Gratz S, Raue F, Becker W. Radiolabeled peptides for targeting of cholecystokinin- B/gastrin receptor expressing tumors: from preclinical development to intitial clinical results.  J Nucl Med. 1999;  40 1029-1044
• 7 Behr T M, Béhé 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 3124-3138
• 8 Behr T M, Béhé M P. 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
• 9 Jakubke H D. Peptide - Chemie und Biologie. Spektrum Akademischer Verlag, Heidelberg 1996
• 10 Krenning E P, Kwekkeboom D J, Pauwels S, Kvols L K, Reubi J C. Somatostatin receptor scintigraphy. In: Freeman LM (ed). Nuclear Medicine Annual 1995. Raven Press, New York 1995; 1-50
• 11 Krenning E P, Bakker W H, Breeman W A, Koper J W, Kooij P P, Ausema L, Lameris J S, Reubi J C, Lamberts S W. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin.  Lancet. 1989;  1 (8632) 242-244
• 12 Lamberts S W, Bakker W H, Reubi J C, Krenning E P. Somatostatin-receptor imaging in the localization of endocrine tumors.  N Engl J Med. 1990;  323 1246-1249
• 13 Virgolini I, Raderer M, Kurtaran A, Angelberger P, Banyai S, Yang Q, Li S, Banyai M, Pidlich J, Niederle B. et al . Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors.  N Engl J Med. 1994;  331 1116-1121
• 14 Behr T M, Jenner N, Radetzky S, Yücekent 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 radiolabeled gastrin.  Eur J Nucl Med. 1998;  25 424-430
• 15 Bolton A E, Hunter W M. The labelling of proteins to high specific radioactivities by conjugation to a ¹²⁵I- containing acylating agent.  Biochem J. 1973;  133 529-539
• 16 Krenning E P, Kwekkeboom D J, Oei H Y, de Jong R J, Dop F J, Reubi J C, Lamberts S W. Somatostatin-receptor scintigraphy in gastro-enteropancreatic tumors. An overview of European results.  Ann N Y Acad Sci. 1994;  733 416-424
• 17 Meares C F, Moi M K, Diril H, Kukis D L, McCall M J, Deshapnde S V, DeNardo S J, Snook D, Epenetos A A. Macrocyclic chelates of radiometals for diagnosis and therapy.  Br J Cancer Suppl. 1990;  10 21-26
• 18 Heppeler A, Froidevaux S, Mäcke H R, 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 Europ J. 1999;  5 1974-1981
• 19 Smith-Jones P M, Stolz B, Bruns C, Albert R, Reist H W, Fridrich R, Mäcke H R. Gallium-67/gallium-68-[DFO]-octreotide - a potential radiopharmaceutical for PET imaging of somatostatin receptor-positive tumors: synthesis and radiolabeling in vitro and preliminary in vivo studies.  J Nucl Med. 1994;  35 317-325
• 20 van de Loosdrecht A A, van Bodegraven A A, Sepers J M, Sindram J W. Long-term follow-up of two patients with metastatic neuroendocrine tumours treated with octreotide.  Neth J Med. 1998;  53 118-123
• 21 Krenning E P, Kwekkeboom D J, Bakker W H, Breeman W A, Kooij P P, Oei H Y, van Hagen M, Postema P T, de Jong M, Reubi J C. et al . Somatostatin receptor scintigraphy with [¹¹¹In-DTPA-D- Phe¹]- and [¹²³I-Tyr³]-octreotide: the Rotterdam experience with more than 1 000 patients.  Eur J Nucl Med. 1993;  20 716-731
• 22 Seregni E, Chiti A, Bombardieri E. Radionuclide imaging of neuroendocrine tumours: biological basis and diagnostic results.  Eur J Nucl Med. 1998;  25 639-658
• 23 Ivancevic V, Wörmann B, Nauck C, Sandrock D, Munz D L, Hiddemann W, Emrich D. Somatostatin receptor scintigraphy in the staging of lymphomas.  Leuk Lymphoma. 1997;  26 107-114
• 24 Denzler B, Reubi J C. Expression of somatostatin receptors in peritumoral veins of human tumors.  Cancer. 1999;  85 188-198
• 25 Behr T M, Gratz S, Markus P M, Dunn R M, Hüfner M, Schauer A, Fischer M, Munz D L, Becker H, Becker W. Anti- carcinoembryonic antigen antibodies versus somatostatin analogs in the detection of metastatic medullary thyroid carcinoma: are carcinoembryonic antigen and somatostatin receptor expression prognostic factors?.  Cancer. 1997;  80 2436-2457
• 26 Bohuslavizki K H, Brenner W, Gunther M, Eberhardt J U, Jahn N, Tinnemeyer S, Wolf H, Sippel C, Clausen M, Gatzemeier U, Henze E. Somatostatin receptor scintigraphy in the staging of small cell lung cancer.  Nucl Med Commun. 1996;  17 191-196
• 27 Behr T M, Gratz S, Markus P M, Dunn R M, Hüfner M, Becker H, Becker W. Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes (”chimney sign”) in occult metastatic medullary thyroid cancer: a typical site of tumor manifestation?.  Eur J Nucl Med. 1997;  24 184-191
• 28 Busnardo B, Girelli M E, Simioni N, Nacamulli D, Bosetto E. Nonparallel patterns of calcitonin and carcinoembryonic antigen levels in the follow-up of medullary thyroid carcinoma.  Cancer. 1984;  53 278-285
• 29 Mendelsohn G, Wells Jr S A, Baylin S B. Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma.  Cancer. 1984;  54 657-662
• 30 Reubi J C, Chayvialle J A, Franc B, Cohen R, Calmettes C, Modigliani E. Somatostatin receptors and somatostatin content in medullary thyroid carcinomas.  Lab Invest. 1991;  64 567-573
• 31 Stoffel M, Jamar F, Donckier J, Hainaut P, Decoster P, Beckers C, Pauwels S. Increased uptake of indium-111 pentetreotide up to 10 years after external thoracic irradiation: report of two cases.  Eur J Nucl Med. 1996;  23 723-726
• 32 Otte A, Jermann E, Béhé M, Goetze M, Bucher H C, Roser H W, Heppeler A, Mueller-Brand J, Maecke H R. DOTATOC: a powerful new tool for receptor-mediated radionuclide therapy.  Eur J Nucl Med. 1997;  24 792-795
• 33 Oka H, Jin L, Reubi J C, Qian X, Scheithauer B W, Fujii K, Kameya T, Lloyd R V. Pituitary adenylate-cyclase-activating polypeptide (PACAP) binding sites and PACAP/vasoactive intestinal polypeptide receptor expression in human pituitary adenomas.  Am J Pathol. 1998;  153 1787-1796
• 34 Virgolini I, Kurtaran A, Raderer M, Leimer M, Angelberger P, Havlik E, Li S, Scheithauer W, Niederle B, Valent P. et al . Vasoactive intestinal peptide receptor scintigraphy.  J Nucl Med. 1995;  36 1732-1739
• 35 Kurtaran A, Leimer M, Kaserer K, Yang Q, Angelberger P, Niederle B, Virgolini I. Combined use of ¹¹¹In-DTPA-D-Phe-¹-octreotide (OCT) and ¹²³I-vasoactive intestinal peptide (VIP) in the localization diagnosis of medullary thyroid carcinoma (MTC).  Nucl Med Biol. 1996;  23 503-507
• 36 Reubi J C, Waser B. Unexpected high incidence of cholecystokinin/gastrin receptors in human medullary thyroid carcinomas.  Int J Cancer. 1996;  67 644-647
• 37 Reubi J C, Schaer J C, Waser B. Cholecystokinin(CCK)-A and CCK- B/gastrin receptors in human tumors.  Cancer Res. 1997;  57 1377-1386
• 38 Smith J P, Stock E A, Wotring M G, McLaughlin P J, Zagon I S. Characterization of the CCK-B/gastrin-like receptor in human colon cancer.  Am J Physiol. 1996;  271 797-805
• 39 Reeve J r. Jr, Eysselein V, Solomon TE, Go VLW, eds. Cholecystokinin. New York: Ann New York Acad Sci Vol 1994, 713
• 40 Hennig I M, Laissue J A, Horisberger U, Reubi J C. Substance P receptors in human primary neoplasms.  Int J Cancer. 1995;  61 786-792
• 41 Van Hagen P M, Breeman W AP, Reubi J C, Postema P TE, van den Anker-Lugtenburg P J, Kwekkeboom D J. et al . Visualization of the thymus by substance P receptor scintigraphy in man.  Eur J Nucl Med. 1996;  23 1508-1513
• 42 Modlin I M, Tang L H. Approaches to the diagnosis of gut neuroendocrine tumors: the last word today.  Gastroenterology. 1997;  112 583-90
• 43 Goeke B, Fehmann H C, Schirra J, Hareter A, Goeke R. Das Darmhormon Glucagon-Like Peptide-1 (glp-1): Aus dem Experiment in die Klinik.  Z Gastroenterol. 1997;  35 (4) 285-294
• 44 Goeke R, Conlon J M. Receptors for glp-1(7-36)amide on rat insulinoma derived cells.  J Endocrin. 1988;  116 357
• 45 Flatt P R, Tan K S, Bailey C J, Powell C J, Swanston-Flatt S K, Marks V. Effects of transplantation and resection of a radiation- induced rat insulinoma on glucose homeostasis and the endocrine pancreas.  Br J Cancer. 1986;  54 685-692
• 46 Crespel A, De Boisvilliers F, Gros L, Kervran A. Effects of Glucagon-Like Peptide-1-(7-36)amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line.  Endocrinol. 1996;  137 (9) 3674-3680
• 47 Gotthardt M, Fischer M, Baltes N, Brandt D, Barth P J, Göke B, Joseph K. Szintigraphische Darstellung von Insulinomen mit Hilfe des Glucagon-Like Peptide-1 (GLP)-1- Analogons J123-Exendin4-[Y39] im Tiermodell.  Nuklearmedizin. 2000;  39 A10
• 48 Gotthardt M, Fischer M, Baltes N, Brandt D, Welcke U, G öke B J, Joseph K. Scintigraphic detection of insulinomas by [I123]-Glucagon-Like Peptide-1 and its analogon [ I123]-Exendin4 [Y39] in a rat tumor model.  J Nucl Med. 2000;  41 (5) suppl 9P
• 49 Gotthardt M, Fischer M, Brandt D, Welcke U, Höffken H, Göke B J, Joseph K. Ist Glucagon-Like Peptide-1 (GLP-1) zur szintigraphischen Insulinom-Diagnostik geeignet? Eine experimentelle Studie an RINm5F-Zellen.  Nuklearmedizin. 2000;  39 A50
• 50 Gotthardt M, Fischer M, Naeher I, Holz J B, Jungclas H, Fritsch H W, Béhé M, Göke B, Joseph K, Behr T M. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results.  Eur J Nucl Med Mol Imaging. 2002;  29 597-606
• 51 Otte A, Mueller- Brand J, Dellas S, Nitzsche E U, Herrmann R, Maecke H R. Yttrium-90-labelled somatostatin-analogue for cancer treatment.  Lancet. 1998;  351 417-418
• 52 Behr T M, Goldenberg D M, Becker W. Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations.  Eur J Nucl Med. 1998;  25 201-212
• 53 Behr T M, Béhé M, Becker W. Diagnostic applications of radiolabeled peptides in nuclear endocrinology.  Q J Nucl Med. 1999;  43 268-280
• 54 Moertel C G, Kvols L k, O’connell M j, Rubin J. et al . Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin.  Cancer. 1991;  68 227-232
• 55 Moertel C G, Lefkopoulos M, Lipsitz M. et al . Streptozocin-doxorubicin, streptozocin-fluorouracil of chlorozotocin in the treatment of advanced islet-cell carcinoma.  N Engl J Med. 1992;  326 519-523
• 56 Arnold R, Wied M, Behr T. Somatostatin analogues in the treatment of endocrine tumours of the gastrointestinal tract.  Expert Opin Pharmacother. 2002;  3 643-656
• 57 Behr T M, Gotthardt M, Becker W, Behe M. Radioiodination of monoclonal antibodies, proteins and peptides for diagnosis and therapy. A review of standardized, reliable and safe procedures for clinical grade levels kBq to GBq in the Göttingen/Marburg experience.  Nuklearmedizin. 2002;  41 71-79
• 58 Albert R, Smith-Jones P, Stolz B. et al . Direct synthesis of [DOTA-Dphe¹]-octreotide and [DOTA-Dphe¹-Tyr³]-octreotide (SMT487): two conjugates for systemic delivery of radiotherapeutical nuclides to somatostatin receptor positive tumours in man.  Bioorg Med Chem Lett. 1998;  8 1207-1210
• 59 Stolz B, Weckbecker G, Smith-Jones P. et al . The somatostatin receptor-targeted radiotherpeutic [⁹⁰Y-DOTA-Dphe^1- Tyr³]octreotide (⁹⁰Y-SMT 487) eradicates experimental rat pancreatic CA 20 948 tumours.  Europ J Nuc Med. 1998;  25 668-674
• 60 Smith-Jones P, Stolz B, Albert R. et al . Synthesis and characterisation of [⁹⁰Y ]- Bz-DTPA-octreotide: a yttrium-90-labelled octreotide analogue for radiotherpy of somatostatin receptor-positive tumours.  Nuc Med Biol. 1998;  25 181-188
• 61 Bakker W H, Albert R, Bruns C. et al . [¹¹¹In-DTPA-D-Phe1]- octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation.  Life Science. 1991;  49 1583-1591
• 62 Slooter G D, Breeman W AP, Marquet R L. et al . Anti-proliferative effect of radiolabelled octreotide in a metastases model in rat liver.  International Journal of Cancer. 1999;  81 767-771
• 63 Stolz B, Bruns C, Albert R. et al .Somatostatin receptor-targeted radiotherapy - preclinical proof of concept. In: Octreotide: The Next Decade. Ed SWS Lamberts Bioscientifica Ltd Bristol 1999; 39-47
• 64 Krenning E P, Valkema R, Kooij P PM. et al . Scintigraphy and radionuclide therapy with [Indium-111- labelled-diethyl triamine penta-acetic acid-D-Phe¹]-octreotide.  Ital J Gastroenterol Hepatol. 1999;  31 suppl. 2 219-23
• 65 Tiensuu Janson E, Eriksson B, Öberg K. et al . Treatment with High Dose [¹¹¹In-DTPA-D-PHE¹ ]-Octreotide in Patients with Neuroendocrine Tumors.  Acta Oncol. 1999;  38 373-377
• 66 Paganeli G, Zoboli S, Cremones M. et al . Receptor-mediated radiotherapy with ⁹⁰Y-DOTA-D-Phe¹-Tyr³-octreotide.  Europ J Nucl Med. 2001;  28 426-434
• 67 Otte A, Herrmann R, Heppeler A. et al . Yttrium-90 DOTATOC: first clinical results.  Europ J Nucl Med. 1999;  26 1439-1447
• 68 Waldherr C, Pless M, Maecke H R. et al . 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
• 69 Breeman W AP, De Jong M, Kwekkeboom D J. et al . Somatostatin receptor-mediated imaging and therapy: basic science, current knowledge, limitations and future perspectives.  Eur J Nucl Med. 2001;  28 1421-1429
• 70 De Jong M, Valkema R, Jamar F. et al . Somatostatin receptor-taregted radionuclide therapy of tumors: preclinical and clinical findings.  Sem Nucl Med. 2002;  32 133-140
• 71 Moll S, Nickeleit V, Mueller-Brand J. et al . A new cause of renal thyrombotic microangiopathy: yttrium-90-DOTATOC internal radiotherapy.  Am J Kidney Dis. 2001;  37 847-851
• 72 Behr T M, Béhé M, Kluge G. et al . Nephrotoxicity versus anti-tumour efficacy in radiopeptide therapy: facts and myths about the Scylla and Charybdis. Eur J Nucl.  Med. 2002;  29 277-279
• 73 Behr T M, Sharkey R M, Juweid M E. et al . Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives.  Cancer Res. 1995;  55 3825-3834
• 74 Behr T M, Sharkey R M, Sgouros G . et al . Overcoming the nephrotoxicity of radiometal-labeled immunoconjugates: improved cancer therapy administered to a nude mouse model in relation to the internal radiation dosimetry.  Cancer. 1997;  80 2591-2610
• 75 Froidevaux S, Heppeler A, Eberle A N. et al . Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy.  Endocrinology. 2000;  141 3304-3312
• 76 Valkema R, De Jong M, Bakker W H. et al . Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience.  Semin Nucl Med. 2002;  32 110-122
• 77 Virgolini I, Britton K, Buscombe J. et al . ¹¹¹In- and ⁹⁰Y-DOTA-Lanreotide: results and implications of the MAURITIUS trial.  Semin Nucl Med. 2002;  32 148-155