Inhibition of gastrin-stimulated growth of gastrointestinal tumour cells by octreotide and the gastrin/cholecystokinin receptor antagonists, proglumide and lorglumide.
The rat pancreatic cell line, AR42J possessed high-affinity gastrin and somatostatin receptors and its growth was stimulated by physiological gastrin-17 concentrations between 5 x 10(-11) mol/l and 10(-9) mol/l as measured by [75Se]selenomethionine uptake. The somatostatin analogue, octreotide (2 x 10(-7) to 2 x 10(-11) mol/l), reduced this stimulated growth. Gastrin-stimulated AR42J growth was also inhibited by proglumide (3 x 10(-4) mol/l) and lorglumide (3 x 10(-5) mol/l) at maximal G17 concentrations of 5 x 10(-11) and 10(-10) mol/l, respectively, and the analogues competed with [125I] gastrin-17 (5 x 10(-10) mol/l) for binding to gastrin receptors on AR42J (50% inhibitory concentrations, less than or equal to 10(-3) mol/l and 4 x 10(-6) mol/l, respectively. Octreotide reduced the basal growth of the human gastric cell line, MKN45G, (which is associated with intracellular gastrin immunoreactivity) in serum-free medium to 73% of control at a concentration of 2 x 10(-8) mol/l, which was reversed by gastrin-17 (10(-10) mol/l). Lorglumide (3 x 10(-5) mol/l) also reduced the basal growth to 30% of control, which was reversed to 78% by 10(-5) mol/l gastrin. Proglumide had no effect on the basal growth of MKN45G.
Cancer Research Campaign Laboratories, University of Nottingham, U.K.
S A
SA
Watson
D L
DL
Morris
L G
LG
Durrant
J F
JF
Robertson
J D
JD
Hardcastle
D000818:Animals; D001665:Binding Sites; D005755:Gastrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D015282:Octreotide / Q000494:pharmacology*; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D005755:Gastrins; D011949:Receptors, Cholecystokinin; D013004:Somatostatin; D011377:Proglumide; C048181:lorglumide; D015282:Octreotide