Pre-clinical evaluation of a new orally-active CCK-2R antagonist, Z-360, in gastrointestinal cancer models.
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.
Grabowska
A M
AM
Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, UK.
Morris
T M
TM
McKenzie
A J
AJ
Kumari
R
R
Hamano
H
H
Emori
Y
Y
Yoshinaga
K
K
Watson
S A
SA
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*
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D043887:Receptor, Cholecystokinin B; C528831:Z-360