Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Die Highlights vom Kongress des American College of Cardiology 2024

Im April diskutierten die Herz-Kreislauf-Spezialisten aus der ganzen Welt auf dem  Kongress des American College of Cardiology (ACC) u.a. neue Therapieansätze bei akutem Myokardinfarkt, koronarer Herzerkrankung, kardiogenem Schock oder Aortenklappenstenose. In unserem Kongress-Dossier haben wir für Sie Berichte über die „Late-Breaking Trials“ und andere wichtige Studien zusammengestellt. 
Erweiterte Suche
Anmelden
nach oben
European Journal of Nuclear Medicine and Molecular Imaging
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 2/2011

01.02.2011 | Original Article

177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi

verfasst von: Christof Seidl, Christine Zöckler, Roswitha Beck, Leticia Quintanilla-Martinez, Frank Bruchertseifer, Reingard Senekowitsch-Schmidtke

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

213Bi-d9MAb-immunoconjugates targeting gastric cancer cells have effectively cured peritoneal carcinomatosis in a nude mouse model following intraperitoneal injection. Because the β-emitter 177Lu has proven to be beneficial in targeted therapy, 177Lu-d9MAb was investigated in this study in order to compare its therapeutic efficacy and toxicity with those of 213Bi-d9MAb.

Methods

Nude mice were inoculated intraperitoneally with HSC45-M2 gastric cancer cells expressing d9-E-cadherin and were treated intraperitoneally 1 or 8 days later with different activities of specific 177Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with nonspecific 177Lu-d8MAb. Therapeutic efficacy was evaluated by monitoring survival for up to 250 days. For evaluation of toxicity, both biodistribution of 177Lu-d9MAb and blood cell counts were determined at different time points and organs were examined histopathologically.

Results

Treatment with 177Lu-immunoconjugates (1.85, 7.4, 14.8 MBq) significantly prolonged survival. As expected, treatment on day 1 after tumour cell inoculation was more effective than treatment on day 8, and specific 177Lu-d9MAb conjugates were superior to nonspecific 177Lu-d8MAb. Treatment with 7.4 MBq of 177Lu-d9MAb was most successful, with 90% of the animals surviving longer than 250 days. However, treatment with therapeutically effective activities of 177Lu-d9MAb was not free of toxic side effects. In some animals lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen but were not observed after treatment with 213Bi-d9MAb at comparable therapeutic efficacy.

Conclusion

The therapeutic efficacy of 177Lu-d9MAb conjugates in peritoneal carcinomatosis is impaired by toxic side effects. Because previous therapy with 213Bi-d9MAb revealed comparable therapeutic efficacy without toxicity it should be preferred for the treatment of peritoneal carcinomatosis.
Literatur
1.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.CrossRefPubMed
2.
Rosenberg R, Nekarda H, Bauer P, Schenck U, Hoefler H, Siewert JR. Free peritoneal tumour cells are an independent prognostic factor in curatively resected stage IB gastric carcinoma. Br J Surg 2006;93:325–31.CrossRefPubMed
3.
Jansen EP, Boot H, Verheij M, van de Velde CJ. Optimal locoregional treatment in gastric cancer. J Clin Oncol 2005;23:4509–17.CrossRefPubMed
4.
Khan FA, Shukla AN. Pathogenesis and treatment of gastric carcinoma: "an up-date with brief review". J Cancer Res Ther 2006;2:196–9.CrossRefPubMed
5.
Yamagata S, Nakata B, Hirakawa K. Dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 may be effective against peritoneal dissemination in gastric cancer. Oncol Rep 2004;12:973–8.PubMed
6.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.CrossRefPubMed
7.
Lim L, Michael M, Mann GB, Leong T. Adjuvant therapy in gastric cancer. J Clin Oncol 2005;23:6220–32.CrossRefPubMed
8.
Illert B, Otto C, Vollmers HP, Hensel F, Thiede A, Timmermann W. Human antibody SC-1 reduces disseminated tumor cells in nude mice with human gastric cancer. Oncol Rep 2005;13:765–70.PubMed
9.
Ohtsu A. Chemotherapy for metastatic gastric cancer: past, present, and future. J Gastroenterol 2008;43:256–64.CrossRefPubMed
10.
Berx G, Becker KF, Höfler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 1998;12:226–37.CrossRefPubMed
11.
Becker KF, Kremmer E, Eulitz M, Becker I, Handschuh G, Schuhmacher C, et al. Analysis of E-cadherin in diffuse-type gastric cancer using a mutation-specific monoclonal antibody. Am J Pathol 1999;155:1803–9.PubMed
12.
Senekowitsch-Schmidtke R, Schuhmacher C, Becker KF, Nikula TK, Seidl C, Becker I, et al. Highly specific tumor binding of a 213Bi-labeled monoclonal antibody against mutant E-cadherin suggests its usefulness for locoregional alpha-radioimmunotherapy of diffuse-type gastric cancer. Cancer Res 2001;61:2804–8.PubMed
13.
Seidl C, Schröck H, Seidenschwang S, Beck R, Schmid E, Abend M, et al. Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death. Eur J Nucl Med Mol Imaging 2005;32:274–85.CrossRefPubMed
14.
Seidl C, Port M, Gilbertz KP, Morgenstern A, Bruchertseifer F, Schwaiger M, et al. 213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe. Mol Cancer Ther 2007;6:2346–59.CrossRefPubMed
15.
Seidl C, Port M, Apostolidis C, Bruchertseifer F, Schwaiger M, Senekowitsch-Schmidtke R, et al. Differential gene expression triggered by highly cytotoxic alpha-emitter-immunoconjugates in gastric cancer cells. Invest New Drugs 2010;28:49–60.CrossRefPubMed
16.
Huber R, Seidl C, Schmid E, Seidenschwang S, Becker KF, Schuhmacher C, et al. Locoregional alpha-radioimmunotherapy of intraperitoneal tumor cell dissemination using a tumor-specific monoclonal antibody. Clin Cancer Res 2003;9(Pt 2):3922s–8s.PubMed
17.
Buchhorn HM, Seidl C, Beck R, Saur D, Apostolidis C, Morgenstern A, et al. Non-invasive visualisation of the development of peritoneal carcinomatosis and tumour regression after 213Bi-radioimmunotherapy using bioluminescence imaging. Eur J Nucl Med Mol Imaging 2007;34:841–9.CrossRefPubMed
18.
Beck R, Seidl C, Pfost B, Morgenstern A, Bruchertseifer F, Baum H, et al. 213Bi-radioimmunotherapy defeats early-stage disseminated gastric cancer in nude mice. Cancer Sci 2007;98:1215–22.CrossRefPubMed
19.
Seidl C, Senekowitsch-Schmidtke R. Treatment of diffuse-type gastric cancer cells using 213Bi-radioimmunoconjugates in vitro and in vivo following intraperitoneal dissemination. Curr Radiopharm 2008;1:215–24.CrossRef
20.
Koppe MJ, Bleichrodt RP, Soede AC, Verhofstad AA, Goldenberg DM, Oyen WJ, et al. Biodistribution and therapeutic efficacy of 125/131I-, 186Re-, 88/90Y-, or 177Lu-labeled monoclonal antibody MN-14 to carcinoembryonic antigen in mice with small peritoneal metastases of colorectal origin. J Nucl Med 2004;45:1224–32.PubMed
21.
Persson M, Gedda L, Lundqvist H, Tolmachev V, Nordgren H, Malmström PU, et al. [177Lu]pertuzumab: experimental therapy of HER-2-expressing xenografts. Cancer Res 2007;67:326–31.CrossRefPubMed
22.
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008;26:2124–30.CrossRefPubMed
23.
Yanagihara K, Ito A, Toge T, Numoto M. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 1993;53:5815–21.PubMed
24.
Fukudome Y, Yanagihara K, Takeichi M, Ito F, Shibamoto S. Characterization of a mutant E-cadherin protein encoded by a mutant gene frequently seen in diffuse-type human gastric carcinoma. Int J Cancer 2000;88:579–83.CrossRefPubMed
25.
Becker KF, Kremmer E, Eulitz M, Schulz S, Mages J, Handschuh G, et al. Functional allelic loss detected at the protein level in archival human tumours using allele-specific E-cadherin monoclonal antibodies. J Pathol 2002;197:567–74.CrossRefPubMed
26.
Milenic DE, Garmestani K, Chappell LL, Dadachova E, Yordanov A, Ma D, et al. In vivo comparison of macrocyclic and acyclic ligands for radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapeutic applications. Nucl Med Biol 2002;29:431–42.CrossRefPubMed
27.
Nikula TK, Curcio MJ, Brechbiel MW, Gansow OA, Finn RD, Scheinberg DA. A rapid, single vessel method for preparation of clinical grade ligand conjugated monoclonal antibodies. Nucl Med Biol 1995;22:387–90.CrossRefPubMed
28.
Bloechl S, Beck R, Seidl C, Morgenstern A, Schwaiger M, Senekowitsch-Schmidtke R. Fractionated locoregional low-dose radioimmunotherapy improves survival in a mouse model of diffuse-type gastric cancer using a 213Bi-conjugated monoclonal antibody. Clin Cancer Res 2005;11:7070s–4s.CrossRefPubMed
29.
Forrer F, Uusijärvi H, Storch D, Maecke HR, Mueller-Brand J. Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC. J Nucl Med 2005;46:1310–6.PubMed
30.
van Essen M, Krenning EP, Kam BL, de Jong M, Valkema R, Kwekkeboom DJ. Peptide-receptor radionuclide therapy for endocrine tumors. Nat Rev Endocrinol 2009;5:382–93.CrossRefPubMed
31.
Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging 2008;35:1847–56.CrossRefPubMed
32.
Rolleman EJ, Forrer F, Bernard B, Bijster M, Vermeij M, Valkema R, et al. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0, Tyr3]octreotate. Eur J Nucl Med Mol Imaging 2007;34:763–71.CrossRefPubMed
33.
Rolleman EJ, Bernard BF, Breeman WA, Forrer F, de Blois E, Hoppin J, et al. Molecular imaging of reduced renal uptake of radiolabelled [DOTA0, Tyr3]octreotate by the combination of lysine and Gelofusine in rats. Nuklearmedizin 2008;47:110–5.PubMed
34.
Mårtensson L, Nilsson R, Ohlsson T, Sjögren HO, Strand SE, Tennvall J. Reduced myelotoxicity with sustained tumor concentration of radioimmunoconjugates in rats after extracorporeal depletion. J Nucl Med 2007;48:269–76.PubMed
35.
Aarts F, Hendriks T, Eek A, Oyen WJ, Bleichrodt RP, Boerman OC. Can antibody galactosylation be used to improve radioimmunotherapy of induced peritoneal carcinomatosis of colonic origin in the rat? Cancer Biother Radiopharm 2009;24:29–34.CrossRefPubMed
36.
Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ. 177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo. Nucl Med Biol 2005;32:269–78.CrossRefPubMed
37.
Kelly MP, Lee ST, Lee FT, Smyth FE, Davis ID, Brechbiel MW, et al. Therapeutic efficacy of 177Lu-CHX-A''-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy. Prostate 2009;69:92–104.CrossRefPubMed
38.
Vallabhajosula S, Goldsmith SJ, Kostakoglu L, Milowsky MI, Nanus DM, Bander NH. Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies: effect of multiple treatments on myelotoxicity. Clin Cancer Res 2005;11(Pt 2):7195s–200s.CrossRefPubMed
39.
Alvarez RD, Partridge EE, Khazaeli MB, Plott G, Austin M, Kilgore L, et al. Intraperitoneal radioimmunotherapy of ovarian cancer with 177Lu-CC49: a phase I/II study. Gynecol Oncol 1997;65:94–101.CrossRefPubMed
40.
Meredith RF, Buchsbaum DJ, Alvarez RD, LoBuglio AF. Brief overview of preclinical and clinical studies in the development of intraperitoneal radioimmunotherapy for ovarian cancer. Clin Cancer Res 2007;13(Pt 2):5643s–5s.CrossRefPubMed
41.
Aarts F, Koppe MJ, Hendriks T, van Eerd JE, Oyen WJ, Boerman OC, et al. Timing of adjuvant radioimmunotherapy after cytoreductive surgery in experimental peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 2007;14:533–40.CrossRefPubMed
Metadaten
Titel
177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi
verfasst von
Christof Seidl
Christine Zöckler
Roswitha Beck
Leticia Quintanilla-Martinez
Frank Bruchertseifer
Reingard Senekowitsch-Schmidtke
Publikationsdatum
01.02.2011
Verlag
Springer-Verlag
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 2/2011
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-010-1639-2

Weitere Artikel der Ausgabe 2/2011

European Journal of Nuclear Medicine and Molecular Imaging 2/2011 Zur Ausgabe

Original Article

Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours

Original Article

Optimal left ventricular lead position assessed with phase analysis on gated myocardial perfusion SPECT

Original Article

Comparison of 18F- and 11C-labeled aryloxyanilide analogs to measure translocator protein in human brain using positron emission tomography

Original Article

Is metal artefact reduction mandatory in cardiac PET/CT imaging in the presence of pacemaker and implantable cardioverter defibrillator leads?

Letter to the Editor

Monitoring response to imatinib using MRI signals in aggressive fibromatosis

Original Article

αvβ3 imaging can accurately distinguish between mature teratoma and necrosis in 18F-FDG-negative residual masses after treatment of non-seminomatous testicular cancer: a preclinical study