Inhibition of pentagastrin-stimulated up-regulation of gastrin receptors and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist.
Inhibition of pentagastrin-stimulated up-regulation of gastrin receptors and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist.
复制标题
DOI：
--
复制
发表时间：
1987-10
期刊：
影响因子：
11.2
通讯作者：
P. Singh;S. Le;R. Beauchamp;C. Townsend;J. Thompson
中科院分区：
文献类型：
--
作者：
P. Singh;S. Le;R. Beauchamp;C. Townsend;J. Thompson
我们最近证实胃泌素通过调节胃泌素受体(GR)来促进小鼠结肠癌(MC-26)的生长。在本研究中，我们测试了GR拮抗剂丙谷胺(PGL)对胃泌素对MC-26肿瘤的营养和GR调节作用的影响。4组小鼠每组12只，接种5×10(4)MC-26细胞，分别注射生理盐水(对照组)、五肽胃泌素(PG)、PGL或同时注射PG+PGL 21天。治疗结束时，记录体重、肿瘤重量、胃底重量和结肠重量，并测量GR。在对照组小鼠肿瘤细胞膜上发现了两种类型的胃泌素结合位点，一种是高亲和力(Kd=<1.0 nM)和低容量(GR)，另一种是容量很高但亲和力很低(Kd=大于0.1微米)(2型胃泌素结合位点)。仅在胃底粘膜和结肠膜上观察到1型GR。PG治疗导致肿瘤重量显著增加，仅上调1型GR。另一方面，PG对胃底粘膜和结肠GR水平没有显著影响，但导致胃底粘膜重量显著增加。PGL完全抑制PG对肿瘤的营养和GR上调作用，但不完全抑制PG刺激的胃底粘膜增重，提示肿瘤和正常组织对PGL的敏感性不同。在没有PG的情况下，PGL对正常胃底粘膜有轻微的营养作用，但对MC-26肿瘤和正常结肠没有作用。在PG存在的情况下，PGL的一个显著作用是显著降低肿瘤和正常胃肠道组织上1型GR与胃泌素的结合亲和力。这可能是PGL干扰PG对MC-26肿瘤和小鼠胃底粘膜作用的另一机制。
We have recently demonstrated that gastrin stimulates growth of mouse colon cancer (MC-26) in vivo by regulation of gastrin receptors (GR). In the present study, we have tested the effect of proglumide (PGL), a GR antagonist, on the trophic and GR-regulatory effects of gastrin on MC-26 tumors. Four groups of 12 mice each were inoculated with 5 X 10(4) MC-26 cells and given injections of either normal saline (control), pentagastrin (PG), PGL, or both PG + PGL for 21 days. At the end of the treatment period, body, tumor, fundic, and colon weights were noted and GR measured. Two types of specific gastrin-binding sites were found on tumor cell membranes of control mice, one with high binding affinity (Kd = less than 1.0 nM) and low capacity (GR), and the other with a very high capacity and a low affinity (Kd = greater than 0.1 microM) (type 2 gastrin-binding sites). Only the type 1 GR were observed on the fundic mucosal and colon membranes. PG treatment resulted in a significant weight increase of the tumors with an up-regulation of only type 1 GR. On the other hand, PG had no significant effect on fundic mucosal and colonic GR levels, but caused a significant increase in fundic mucosal weights. PGL completely inhibited both the trophic and GR up-regulatory effects of PG on tumors, but incompletely reduced the PG-stimulated fundic mucosal weight gain, indicating differential sensitivity of tumor and normal tissues to PGL. PGL, in the absence of PG, was slightly trophic for normal fundic mucosa, but had no effect on MC-26 tumors and normal colon. The one striking effect of PGL, in the presence of PG, was the significant lowering of the binding affinity of type 1 GR for gastrin on both the tumor and normal gastrointestinal tissues. This effect may be another mechanism by which PGL interferes with the actions of PG on MC-26 tumors and fundic mucosa of mice.