Inhibition of pentagastrin-stimulated up-regulation of gastrin receptor and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist

Pomila Singh, S. Le, R. D. Beauchamp, Courtney Townsend, J. C. Thompson

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 104 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 (K(d)=<1.0 nM) and low capacity (GR), and the other with a very high capacity and a low affinity (K(d)=>0.1 μM) (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.

Original languageEnglish (US)
Pages (from-to)5000-5004
Number of pages5
JournalCancer Research
Volume47
Issue number19
StatePublished - 1987

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Proglumide
Cholecystokinin B Receptor
Pentagastrin
Colon
Up-Regulation
Gastrins
Growth
Neoplasms
Mucous Membrane
Binding Sites
Weights and Measures
Tumor Burden
Colonic Neoplasms
Weight Gain
Cell Membrane

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inhibition of pentagastrin-stimulated up-regulation of gastrin receptor and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist. / Singh, Pomila; Le, S.; Beauchamp, R. D.; Townsend, Courtney; Thompson, J. C.

In: Cancer Research, Vol. 47, No. 19, 1987, p. 5000-5004.

Research output: Contribution to journalArticle

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abstract = "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 104 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 (K(d)=<1.0 nM) and low capacity (GR), and the other with a very high capacity and a low affinity (K(d)=>0.1 μM) (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.",
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