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Pre-clinical evaluation of a new orally-active CCK-2R antagonist, Z-360, in gastrointestinal cancer models

A M Grabowska1, T M Morris, A J McKenzie

  • 1Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, UK.

Regulatory Peptides
|October 27, 2007
PubMed
Abstract

Insights

The novel gastrin/cholecystokinin-2 receptor (CCK-2R) antagonist Z-360 shows pre-clinical anti-tumour effects. This orally-active compound demonstrated efficacy in various gastrointestinal malignancy models.

Area of Science:

  • Gastroenterology
  • Oncology
  • Pharmacology

Background:

  • Gastrin plays a role in gastrointestinal (GI) malignancy.
  • Pre-clinical evaluation of Z-360, a novel, orally-active gastrin/cholecystokinin-2 receptor (CCK-2R) antagonist, is presented.

Purpose of the Study:

  • To evaluate the pre-clinical efficacy of Z-360 as a CCK-2R antagonist in gastrointestinal malignancy models.
  • To assess the in vivo anti-tumour effects and tolerability of Z-360.

Main Methods:

  • Used (125)I gastrin-17 displacement and G17-stimulated calcium assays in CCK-2R-transfected cell lines.
  • Assessed Akt phosphorylation by Western blotting and investigated Z-360 efficacy in three human xenograft models.
  • Examined microvessel density and apoptosis via immunohistochemistry in xenograft models.

Main Results:

  • Z-360 inhibited (125)I G17 binding and G17-stimulated signaling, with reduced Akt phosphorylation reversed by G17.
  • Demonstrated increased survival in a gastric ascites model (p=0.011) and decreased tumor growth in a hepatic metastasis model (81%, p=0.02).
  • In an orthotopic pancreatic model, Z-360 combined with gemcitabine significantly decreased tumor weight (84%, p=0.002), increased apoptosis, and reduced microvessel density.

Conclusions:

  • Z-360 exhibits high sub-nanomolar affinity for classical CCK-2R.
  • The orally-active CCK-2R antagonist Z-360 is well tolerated in vivo.
  • Z-360 exerts a significant anti-tumour effect in pre-clinical models of GI malignancy.

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