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.