Inhibition of pentagastrin-stimulated up-regulation of gastrin receptors and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist.
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.
D000818:Animals; D003106:Colon / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005755:Gastrins / Q000378:metabolism; D005973:Glutamine / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D010418:Pentagastrin / Q000494:pharmacology*; D011377:Proglumide / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000187:drug effects*
D005755:Gastrins; D011949:Receptors, Cholecystokinin; D005973:Glutamine; D010418:Pentagastrin; D011377:Proglumide