title: Inhibitory effects of the gastrin receptor antagonist (L-365,260) on gastrointestinal tumor cells.
abstract: A selective gastrin receptor (GR) antagonist, L-365,260 is bound to the GR on AR42J cells with a potency 7.5-fold less than G17 (50% inhibitory concentration [IC50] G17, 6 x 10(-9) mol/l; IC50 L365-260, 4.5 x 10(-8) mol/l). G17 is mitogenic for AR42J cells, as assessed by 75Se-selenomethionine uptake and L-365,260 at concentrations of 2.5 x 10(-6) mol/l and 2.5 x 10(-7) mol/l, (55X and 5.5 X the dose required to displace 50% 125I G17, respectively), and reduced optimal G17 stimulated mitogenesis in 75% of experiments. The basal growth of two human colon cancer cell lines, LoVo and C146 was reduced by L-365,260 (2.5 x 10(-7) mol/l) after 5 days of treatment to 44% and 64% of the control, respectively. However, inhibition was followed by a rebound of growth to control levels. The growth of AR42J xenografts in nude mice was increased by administration of G17 (10 micrograms/mouse/d, P less than 0.027). This increase was blocked by coadministration of oral L-365,260 (5 mg/kg/d, P less than 0.034). L-365,260 could be an important therapeutic agent in slowing the growth of GR-positive, G17-sensitive gastrointestinal tumors.
authors.affiliation: Cancer Research Campaign Laboratories, University of Nottingham, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Watson
authors.forename: L
authors.initials: L
authors.lastname: Durrant
authors.forename: P
authors.initials: P
authors.lastname: Elston
authors.forename: D
authors.initials: D
authors.lastname: Morris
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D001570:Benzodiazepinones / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D001570:Benzodiazepinones; D010671:Phenylurea Compounds; C058121:L 365260