Jean Claude Reubi1, Beatrice Waser2, Helmut Mäcke3, Jean Rivier4. 1. Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland reubi@pathology.unibe.ch. 2. Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland. 3. Department of Nuclear Medicine, University of Freiburg, Freiburg, Germany; and. 4. The Salk Institute for Biological Studies, La Jolla, California.
Abstract
There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst2) antagonists are better tools to target neuroendocrine tumors (NETs) than sst2 agonists. Indeed, antagonists bind to a greater number of sst2 sites than agonists. Whether sst2 antagonists could be used successfully to target non-NETs, expressing low sst2 density, is unknown. Here, we compare quantitatively 125I-JR11 sst2 antagonist binding in vitro with that of the sst2 agonist 125I-Tyr3-octreotide in large varieties of non-NET and NET. METHODS: In vitro receptor autoradiography was performed with 125I-JR11 and 125I-Tyr3-octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues as well as NETs as reference. RESULTS: In general, 125I-JR11 binds to many more sst2 sites than 125I-Tyr3-octreotide. In 13 breast cancers, 8 had a low binding (mean density, 844 ± 168 dpm/mg of tissue) with the agonist whereas 12 had a high binding (mean density, 4,447 ± 1,128 dpm/mg of tissue) with the antagonist. All 12 renal cell cancers showed a low binding of sst2 with the agonist (mean density, 348 ± 49 dpm/mg of tissue) whereas all cases had a high sst2 binding with the antagonist (mean density, 3,777 ± 582 dpm/mg of tissue). One of 5 medullary thyroid cancers was positive with the agonist, whereas 5 of 5 were positive with the antagonist. In 15 non-Hodgkin lymphomas, many more sst2 sites were labeled with the antagonist than with the agonist. In 14 prostate cancers, none had sst2 binding with the agonist and only 4 had a weak binding with the antagonist. None of 17 colon cancers showed sst2 sites with the agonist, and only 3 cases were weakly positive with the antagonist. In the various tumor types, adjacent sst2-expressing tissues such as vessels, lymphocytes, nerves, mucosa, or stroma were more strongly labeled with the antagonist than with the agonist. The reference NET cases, incubated with a smaller amount of tracer, were also found to have many more sst2 sites measured with the antagonist. CONCLUSION: All renal cell cancers and most breast cancers, non-Hodgkin lymphomas, and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst2 by sst2 antagonists, comparable to NET radiotargeting with sst2 agonists.
There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst2) antagonists are better tools to target neuroendocrine tumors (NETs) than sst2 agonists. Indeed, antagonists bind to a greater number of sst2 sites than agonists. Whether sst2 antagonists could be used successfully to target non-NETs, expressing low sst2 density, is unknown. Here, we compare quantitatively 125I-JR11 sst2 antagonist binding in vitro with that of the sst2 agonist 125I-Tyr3-octreotide in large varieties of non-NET and NET. METHODS: In vitro receptor autoradiography was performed with 125I-JR11 and 125I-Tyr3-octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues as well as NETs as reference. RESULTS: In general, 125I-JR11 binds to many more sst2 sites than 125I-Tyr3-octreotide. In 13 breast cancers, 8 had a low binding (mean density, 844 ± 168 dpm/mg of tissue) with the agonist whereas 12 had a high binding (mean density, 4,447 ± 1,128 dpm/mg of tissue) with the antagonist. All 12 renal cell cancers showed a low binding of sst2 with the agonist (mean density, 348 ± 49 dpm/mg of tissue) whereas all cases had a high sst2 binding with the antagonist (mean density, 3,777 ± 582 dpm/mg of tissue). One of 5 medullary thyroid cancers was positive with the agonist, whereas 5 of 5 were positive with the antagonist. In 15 non-Hodgkin lymphomas, many more sst2 sites were labeled with the antagonist than with the agonist. In 14 prostate cancers, none had sst2 binding with the agonist and only 4 had a weak binding with the antagonist. None of 17 colon cancers showed sst2 sites with the agonist, and only 3 cases were weakly positive with the antagonist. In the various tumor types, adjacent sst2-expressing tissues such as vessels, lymphocytes, nerves, mucosa, or stroma were more strongly labeled with the antagonist than with the agonist. The reference NET cases, incubated with a smaller amount of tracer, were also found to have many more sst2 sites measured with the antagonist. CONCLUSION: All renal cell cancers and most breast cancers, non-Hodgkin lymphomas, and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst2 by sst2 antagonists, comparable to NET radiotargeting with sst2 agonists.
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