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.
Department of Surgery Queen's Medical Centre, Nottingham University, UK.
S A
SA
Watson
T L
TL
Clifford
R J
RJ
Steele
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