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.
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.
Kobayashi
Nobuyoshi
N
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, 2512-1 Oshikiri, Kumagaya, Saitama 360-0111, Japan.
Seto
Koichi
K
Orikawa
Yuki
Y
Hamano
Hiroki
H
Yoshinaga
Koji
K
Takei
Mineo
M
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
D001570:Benzodiazepinones; D043887:Receptor, Cholecystokinin B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C528831:Z-360; D003841:Deoxycytidine; D000093542:Gemcitabine