Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis
Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes th...
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| description | Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.
To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.
We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.
Netazepide was safe and well tolerated. Abundances of CgA (p |
| doi_str_mv | 10.1371/journal.pone.0076462 |
| format | Article |
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To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.
We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.
Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.
The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.
European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0076462</identifier><identifier>PMID: 24098507</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aged ; Analysis ; Animal models ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Benzodiazepinones - pharmacology ; Benzodiazepinones - therapeutic use ; Bioavailability ; Biological markers ; Biomarkers ; Biomarkers - blood ; Biomarkers - metabolism ; Biopsy ; Cell constituents ; Cell culture ; Cholecystokinin ; Chromogranin A - blood ; Clinical trials ; Drug dosages ; Endoscopy ; Female ; Gastric Mucosa - metabolism ; Gastric Mucosa - pathology ; Gastrin ; Gastrins - blood ; Gastritis ; Gastritis, Atrophic - complications ; Gastroenterology ; Gastroscopy ; Gene expression ; Histidine ; Histidine decarboxylase ; Humans ; Hyperplasia ; Male ; Matrilysin ; Matrix metalloproteinase ; Medical research ; Medicine ; Metalloproteinase ; Middle Aged ; Nets ; Neuroendocrine tumors ; Neuroendocrine Tumors - complications ; Neuroendocrine Tumors - drug therapy ; Neuroendocrine Tumors - pathology ; Patients ; Phenylurea Compounds - pharmacology ; Phenylurea Compounds - therapeutic use ; Physiology ; Receptor, Cholecystokinin B - antagonists & inhibitors ; Rodents ; Stomach Neoplasms - complications ; Stomach Neoplasms - drug therapy ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - pathology ; Surveillance ; Treatment Outcome ; Trinucleotide repeats ; Tumor Burden ; Tumors</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e76462-e76462</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Moore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Moore et al 2013 Moore et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7a5fec250547a6e486fa69648e65a6906a4b20a5a1229c0093e847198a5dca113</citedby><cites>FETCH-LOGICAL-c692t-7a5fec250547a6e486fa69648e65a6906a4b20a5a1229c0093e847198a5dca113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788129/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788129/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24098507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moore, Andrew R</creatorcontrib><creatorcontrib>Boyce, Malcolm</creatorcontrib><creatorcontrib>Steele, Islay A</creatorcontrib><creatorcontrib>Campbell, Fiona</creatorcontrib><creatorcontrib>Varro, Andrea</creatorcontrib><creatorcontrib>Pritchard, D Mark</creatorcontrib><title>Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description><![CDATA[Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.
To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.
We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.
Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.
The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.
European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.]]></description><subject>Aged</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Benzodiazepinones - pharmacology</subject><subject>Benzodiazepinones - therapeutic use</subject><subject>Bioavailability</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Biomarkers - blood</subject><subject>Biomarkers - metabolism</subject><subject>Biopsy</subject><subject>Cell constituents</subject><subject>Cell culture</subject><subject>Cholecystokinin</subject><subject>Chromogranin A - blood</subject><subject>Clinical trials</subject><subject>Drug dosages</subject><subject>Endoscopy</subject><subject>Female</subject><subject>Gastric Mucosa - metabolism</subject><subject>Gastric Mucosa - pathology</subject><subject>Gastrin</subject><subject>Gastrins - blood</subject><subject>Gastritis</subject><subject>Gastritis, Atrophic - complications</subject><subject>Gastroenterology</subject><subject>Gastroscopy</subject><subject>Gene expression</subject><subject>Histidine</subject><subject>Histidine decarboxylase</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Male</subject><subject>Matrilysin</subject><subject>Matrix metalloproteinase</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Metalloproteinase</subject><subject>Middle Aged</subject><subject>Nets</subject><subject>Neuroendocrine tumors</subject><subject>Neuroendocrine Tumors - complications</subject><subject>Neuroendocrine Tumors - drug therapy</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Patients</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Phenylurea Compounds - therapeutic use</subject><subject>Physiology</subject><subject>Receptor, Cholecystokinin B - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals (DOAJ)</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moore, Andrew R</au><au>Boyce, Malcolm</au><au>Steele, Islay A</au><au>Campbell, Fiona</au><au>Varro, Andrea</au><au>Pritchard, D Mark</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e76462</spage><epage>e76462</epage><pages>e76462-e76462</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract><![CDATA[Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.
To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.
We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.
Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.
The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.
European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.]]></abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24098507</pmid><doi>10.1371/journal.pone.0076462</doi><tpages>e76462</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-10, Vol.8 (10), p.e76462-e76462 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1438700427 |
| source | Directory of Open Access Journals (DOAJ); Public Library of Science (PLoS) Journals Open Access; MEDLINE; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Aged Analysis Animal models Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Benzodiazepinones - pharmacology Benzodiazepinones - therapeutic use Bioavailability Biological markers Biomarkers Biomarkers - blood Biomarkers - metabolism Biopsy Cell constituents Cell culture Cholecystokinin Chromogranin A - blood Clinical trials Drug dosages Endoscopy Female Gastric Mucosa - metabolism Gastric Mucosa - pathology Gastrin Gastrins - blood Gastritis Gastritis, Atrophic - complications Gastroenterology Gastroscopy Gene expression Histidine Histidine decarboxylase Humans Hyperplasia Male Matrilysin Matrix metalloproteinase Medical research Medicine Metalloproteinase Middle Aged Nets Neuroendocrine tumors Neuroendocrine Tumors - complications Neuroendocrine Tumors - drug therapy Neuroendocrine Tumors - pathology Patients Phenylurea Compounds - pharmacology Phenylurea Compounds - therapeutic use Physiology Receptor, Cholecystokinin B - antagonists & inhibitors Rodents Stomach Neoplasms - complications Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Surveillance Treatment Outcome Trinucleotide repeats Tumor Burden Tumors |
| title | Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis |
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