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.
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.
Piontek
M K
MK
Department of Gastroenterology, University Hospital, Duesseldorf, Germany.
Hengels
K J
KJ
D016475:3T3 Cells / Q000187:drug effects; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005755:Gastrins / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010671:Phenylurea Compounds; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D001570:Benzodiazepinones; D005755:Gastrins; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; C053737:loxiglumide; D011377:Proglumide