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: A M Grabowska, T M Morris, A J McKenzie, R Kumari, H Hamano, Y Emori, K Yoshinaga, S A Watson
• Journal: Regulatory peptides (Regul Pept) Vol. 146 Issue 1-3 Pg. 46-57 (Feb 07 2008) ISSN: 0167-0115 [Print] Netherlands
• PMID: 17961733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzodiazepinones
• Receptor, Cholecystokinin B
• Z-360

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Benzodiazepinones (chemistry, pharmacology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Gastrointestinal Neoplasms (drug therapy)
• Humans
• Molecular Structure
• Receptor, Cholecystokinin B (antagonists & inhibitors)