Differential mode of action of high- and low-affinity CCK/gastrin receptor antagonists in growth inhibition of gastrin--responsive human gastric adenocarcinoma cells in vitro

Anticancer Res. May-Jun 1993;13(3):715-20.

Abstract

Exogenous gastrin exerted a trophic effect on the human gastric adenocarcinoma cell line AGS with a maximum stimulation at 100 pM. The CCK/gastrin receptor antagonists proglumide and loxiglumide dose-dependently inhibited spontaneous growth of AGS gastric cancer cells with half maximal inhibition at 8 mM and 200 microM, respectively. This growth inhibition could not be reversed by coincubation with gastrin. In control experiments with murine 3T3 fibroblasts gastrin had no growth-promoting effect. Proglumide and loxiglumide, however, exerted the same growth inhibition on 3T3 cells as they did on gastrin-responsive AGS tumor cells, suggesting a gastrin receptor independent mode of action. L 365, 260 had no effect on the spontaneous growth of AGS tumor cells, but abolished growth stimulation by exogenous gastrin in a dose-dependent manner. These results suggest that only the high-affinity gastrin receptor antagonist L 365, 260 acts by a specific, i.e. selective, reversible, and competitive mode of action. In contrast, the low affinity CCK/gastrin receptor antagonists proglumide and loxiglumide obviously have an irreversible and non-competitive mode of action with respect to growth inhibition of AGS gastric cancer cells, which is not mediated by gastrin receptors.

MeSH terms

  • 3T3 Cells / drug effects
  • Adenocarcinoma / pathology*
  • Animals
  • Benzodiazepinones / pharmacology*
  • Cell Division / drug effects
  • Gastrins / pharmacology*
  • Humans
  • Mice
  • Phenylurea Compounds*
  • Proglumide / analogs & derivatives*
  • Proglumide / pharmacology*
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Stomach Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • Benzodiazepinones
  • Gastrins
  • Phenylurea Compounds
  • Receptors, Cholecystokinin
  • L 365260
  • loxiglumide
  • Proglumide