Inhibitory effects of the gastrin receptor antagonist CR2093 on basal, gastrin-stimulated and growth factor-stimulated growth of the rat pancreatic cell line AR42J.
AR42J, a rat pancreatic cell line expressing receptors for both gastrin and epidermal growth factor (EGF), has been used to examine the effect of the gastrin receptor antagonist CR2093 on basal, gastrin-17 (G17), EGF and transforming growth factor (TGF)-alpha stimulated growth in vitro. In serum-free conditions, CR2093 reduced the basal growth of AR42J at a concentration known to displace physiological levels of G17 from gastrin receptors and this effect was reversed by G17 at 1 x 10(-9) M. Alone, G17 had little effect on growth, but EGF and TGF-alpha stimulated growth to 181 and 176% of control values, respectively, and marked synergy was observed when G17 was used in combination with both EGF (212%) and TGF-alpha (259%). When CR2093 was added, the synergistic effects of the G17/EGF and G17/TGF-alpha combinations were reduced to basal levels. In addition, CR2093 inhibited the growth stimulation induced by EGF and TGF-alpha alone. When the ability of CR2093 to bind to EGF receptors was assessed in a ligand binding assay, it was found that the antagonist displaced up to 23% of labeled EGF. Thus CR2093 has potent inhibitory effects on the basal growth of AR42J which can be reversed by G17. It can also inhibit type 1 growth factor-stimulated growth, but although this action may in part be related to the antagonist's ability to inhibit binding to the EGF receptor, other mechanisms may be involved.
Watson
S A
SA
Department of Surgery Queen's Medical Centre, Nottingham University, UK.
Clifford
T L
TL
Steele
R J
RJ
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004396:Coloring Agents; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005755:Gastrins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D010190:Pancreatic Neoplasms / Q000473:pathology*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013778:Tetrazolium Salts; D013844:Thiazoles; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D004396:Coloring Agents; D005755:Gastrins; D006131:Growth Inhibitors; D006133:Growth Substances; D007457:Iodine Radioisotopes; D011949:Receptors, Cholecystokinin; D013778:Tetrazolium Salts; D013844:Thiazoles; D016211:Transforming Growth Factor alpha; C075449:CR 2093; D004815:Epidermal Growth Factor; C022616:thiazolyl blue