title: Pre-clinical evaluation of a new orally-active CCK-2R antagonist, Z-360, in gastrointestinal cancer models.
abstract: BACKGROUND
  Gastrin has a role in gastrointestinal (GI) malignancy. This study provides pre-clinical evaluation of a novel, orally-active gastrin/cholecystokinin-2 receptor (CCK-2R) antagonist, Z-360.
  
  
  METHODS
  (125)I gastrin-17 (G17) displacement and G17-stimulated calcium assays were used in classical CCK-2R-transfected cell lines. Akt phosphorylation was assessed by Western blotting. Z-360 efficacy in vivo was evaluated in three human xenograft models, and microvessel density and apoptosis in these models were investigated by immunohistochemistry.
  
  
  RESULTS
  Z-360 inhibited (125)I G17 binding to cells expressing CCK-2R, and G17-stimulated signalling. Reduced Akt phosphorylation in an oesophageal cell-line treated with Z-360 was reversed by co-treatment with G17. Z-360 increased survival in a gastric ascites model (p=0.011) and decreased tumour growth in a hepatic metastasis model (81%, p=0.02). In an orthotopic pancreatic model, Z-360 combined with gemcitabine decreased final tumour weight compared to single agents (84%, p=0.002) and there was increased apoptosis and decreased microvessel density in ex vivo tumour tissue.
  
  
  CONCLUSIONS
  These results show that the orally-active CCK-2R antagonist, Z-360 has high sub-nM affinity for classical CCK-2R, is well tolerated in vivo and exerts an anti-tumour effect.
authors.affiliation: Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Grabowska
authors.forename: T M
authors.initials: TM
authors.lastname: Morris
authors.forename: A J
authors.initials: AJ
authors.lastname: McKenzie
authors.forename: R
authors.initials: R
authors.lastname: Kumari
authors.forename: H
authors.initials: H
authors.lastname: Hamano
authors.forename: Y
authors.initials: Y
authors.lastname: Emori
authors.forename: K
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: S A
authors.initials: SA
authors.lastname: Watson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D015394:Molecular Structure; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D043887:Receptor, Cholecystokinin B; C528831:Z-360