Inhibition of gastrin-stimulated cell proliferation by the CCK-B/gastrin receptor ligand CI-988.
Inhibition of gastrin-stimulated cell proliferation by the CCK-B/gastrin receptor ligand CI-988.
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CCK-B/胃泌素受体配体 CI-988 抑制胃泌素刺激的细胞增殖。
DOI：
10.1016/s0278-6915(98)00119-7
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
L. Bestervelt
中科院分区：
文献类型：
--
作者：
L. Dethloff;B. Barr;L. Bestervelt
胃肠激素胃泌素是促氧粘膜的营养因子，也是胃酸的促分泌剂。在临床前毒理学研究CI-988中，一种对CCK- b /胃泌素受体具有纳米级亲和力的肽类胆囊收缩素（CCK）配体导致食食猴胃腺变性和粘膜萎缩，这可能与预期的抑制胃泌素对胃粘膜营养作用的药理学结果一致。由于实验使用非人类灵长类动物的费用和难度，我们以AR42J大鼠胰腺肿瘤细胞系为模型，研究了CI-988对胃泌素刺激细胞增殖相关信号转导通路的影响。之所以选择AR42J细胞系，是因为它已知表达CCK-B/胃泌素受体，并且在体外对胃泌素的促生长作用有反应。胃泌素-17在1 nm作用24h和96 h后对AR42J细胞的增殖刺激分别比对照高26%和104%。1 nm的CI-988对基底细胞增殖率没有明显影响，但在处理24小时和96小时后，胃泌素-17刺激的细胞增殖率分别下降13%和47%，与胃泌素受体的竞争性拮抗一致。由于胃泌素对AR42J细胞的营养作用与细胞内钙（[Ca2+]i）动员和/或环AMP有关，因此我们也研究了CI-988对这些第二信使的影响。胃泌素-17在10 nm时对（[Ca2+]i）和cAMP均有刺激，而单独使用CI-988在100 nm时没有作用，但抑制了这两种介质在胃泌素刺激下的增加。因此，以AR42J胰腺肿瘤细胞系为模型，二肽样CCK-B/胃泌素受体配体CI-988在体外对胃泌素受体刺激的信号转导通路和细胞增殖起拮抗剂作用。
The gastrointestinal hormone gastrin functions as a trophic factor for oxyntic mucosa as well as a secretagogue for gastric acid. In preclinical toxicology studies CI-988, a peptoid cholecystokinin (CCK) ligand with nanomolar affinity for the CCK-B/gastrin receptor, caused gastric gland degeneration and mucosal atrophy in cynomolgus monkeys, perhaps consistent with an expected pharmacological outcome of inhibition of the trophic effect of gastrin on stomach mucosa. Because of the expense and difficulty associated with experimental use of non-human primates, we investigated the effects of CI-988 on signal transduction pathways associated with gastrin-stimulated cell proliferation using the AR42J rat pancreatic tumour cell line as a model. The AR42J cell line was selected because it is known to express the CCK-B/gastrin receptor and because it is responsive to the growth promoting effects of gastrin in vitro. Gastrin-17 at 1 nm stimulated proliferation of AR42J cells 26% and 104% above control after 24 and 96 hours, respectively. CI-988 at 1 nm had no apparent effect on basal cell proliferation rates, but decreased gastrin-17 stimulated cell proliferation 13% and 47%, respectively, after 24 and 96 hours of treatment, consistent with competitive antagonism at the gastrin receptor. Because the trophic effect of gastrin towards AR42J cells has been linked to intracellular calcium ([Ca2+]i) mobilization and/or cyclic AMP, the effect of CI-988 on these second messengers were also investigated. Gastrin-17 at 10 nm stimulated both ([Ca2+]i) and cAMP, while CI-988 alone at 100 nm had no effect, but blocked the gastrin-stimulated increases in both mediators. Therefore, using the AR42J pancreatic tumour cell line as a model, the dipeptoid CCK-B/gastrin receptor ligand CI-988 behaves as an antagonist towards gastrin receptor-stimulated signal transduction pathways and cell proliferation in vitro.
胃泌素对人结肠癌细胞中 3,5-环单磷酸腺苷、细胞内钙和磷脂酰肌醇水解的影响。
影响因子：
11.2
作者：
Ishizuka,J;TownsendJr,CM;Bold,RJ;Martinez,J;Rodriguez,M;Thompson,JC
通讯作者：
Thompson,JC
丙谷胺抑制五肽胃泌素的营养作用。
DOI：
10.1152/ajpgi.1984.246.1.g62
发表时间：
1984
期刊：
The American journal of physiology
影响因子：
--
作者：
Johnson,LR;Guthrie,PD
通讯作者：
Guthrie,PD
胆囊收缩素 B 受体拮抗剂家族的胆囊收缩素 A 受体激动剂活性表征。
DOI：
--
发表时间：
1994
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
BlevinsJr,GT;vandeWesterlo,EM;Yule,DI;Williams,JA
通讯作者：
Williams,JA