Z-360, a novel cholecystokinin-2/gastrin receptor antagonist, inhibits gemcitabine-induced expression of the vascular endothelial growth factor gene in human pancreatic cancer cells.

Abstract

Z-360 is a novel cholecystokinin (CCK)-2/gastrin receptor antagonist that is being developed for the treatment of pancreatic adenocarcinoma in combination with gemcitabine. A previous study shows that the co-administration of Z-360 with gemcitabine significantly prolonged the survival of mice with orthotopically implanted human pancreatic adenocarcinoma cell lines. To clarify the therapeutic effects of Z-360 in combined with gemcitabine, we analyzed gene expression. When gemcitabine was administered, CCK-2/gastrin receptor expression was induced in an orthotropic xenograft model; the result indicating that Z-360 could act on gemcitabine-sensitive cells. Both in vitro and in vivo studies showed that gemcitabine increased the expression of vascular endothelial growth factor A (VEGFA), a prognostic factor for survival in pancreatic cancer, while Z-360 suppressed this induction of VEGFA gene expression. These results help to explain how Z-360 prolongs survival when used in combination with gemcitabine.

• Authors: Nobuyoshi Kobayashi, Koichi Seto, Yuki Orikawa, Hiroki Hamano, Koji Yoshinaga, Mineo Takei
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 33 Issue 2 Pg. 216-22 ( 2010) ISSN: 1347-5215 [Electronic] Japan
• PMID: 20118543 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzodiazepinones
• Receptor, Cholecystokinin B
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Z-360
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Benzodiazepinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Receptor, Cholecystokinin B (antagonists & inhibitors, physiology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis, genetics)
• Xenograft Model Antitumor Assays (methods)
• Gemcitabine