奈妥匹肽，一种胃泌素受体拮抗剂，在一项针对慢性萎缩性胃炎患者的非随机试验中，可使肿瘤标志物正常化，并使 1 型胃神经内分泌肿瘤消退。
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.
机构信息
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom ; Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
出版信息
PLoS One. 2013 Oct 1;8(10):e76462. doi: 10.1371/journal.pone.0076462. eCollection 2013.
INTRODUCTION
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.
AIM
To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
TRIAL REGISTRATION
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.
简介
自身免疫性慢性萎缩性胃炎（CAG）导致胃酸分泌减少和胃泌素升高，这可能导致肠嗜铬样（ECL）细胞增生和胃神经内分泌肿瘤（1 型胃 NETs）。大多数表现为惰性，但一些较大的肿瘤会转移。切除导致胃泌素升高的源头——胃大部切除术，通常会导致肿瘤消退。非临床和健康受试者研究表明，netazepide（YF476）是一种有效的、高度选择性和口服活性的胃泌素/CCK-2 受体拮抗剂。此外，它在由胃泌素升高引起的 ECL 细胞肿瘤的动物模型中也是有效的。
目的
评估 netazepide 对 1 型胃 NETs 患者肿瘤生物标志物数量和大小的影响。
方法
我们对 8 例多发性肿瘤且循环胃泌素和嗜铬粒蛋白 A（CgA）浓度升高的患者进行了为期 12 周的口服 netazepide 开放试验研究，并在 12 周后进行了随访。在 0、6、12 和 24 周时，我们进行了胃镜检查，计数和测量肿瘤，并进行活检以评估几种 ECL 细胞成分的丰度。在 0、3、6、9、12 和 24 周时，我们测量了循环胃泌素和 CgA，并评估了安全性和耐受性。
结果
netazepide 安全且耐受良好。CgA（p<0.05）、组氨酸脱羧酶（p<0.05）和基质金属蛋白酶-7（p<0.10）的丰度在 6 和 12 周时降低，但在随访时再次升高。同样，血浆 CgA 在 3 周时降低（p<0.01），直到 12 周时仍保持降低，但在随访时再次升高。肿瘤数量减少，最大肿瘤的大小在 12 周时（p<0.05）变小，随访时仍保持较小。血清胃泌素不受影响。
结论
netazepide 降低了生物标志物、血浆 CgA、肿瘤数量和大小，表明 1 型 NETs 是胃泌素依赖性肿瘤。netazepide 未能进一步增加血清胃泌素，这与胃酸缺乏一致。netazepide 可能是治疗 1 型 NETs 的一种新的潜在药物。需要进行更长时间的对照试验。
试验注册
欧盟 EudraCT 数据库 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.
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