Effect of Z-360, a novel orally active CCK-2/gastrin receptor antagonist on tumor growth in human pancreatic adenocarcinoma cell lines in vivo and mode of action determinations in vitro

Purpose Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [( R )-(−)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepin-3-yl}u...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2008-04, Vol.61 (5), p.883-892
Main Authors: Kawasaki, Daisuke, Emori, Yutaka, Eta, Runa, Iino, Yuka, Hamano, Hiroki, Yoshinaga, Koji, Tanaka, Takao, Takei, Mineo, Watson, Susan A.
Format: Article
Language:English
Subjects:
Adenocarcinoma - drug therapy
Administration, Oral
Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Benzodiazepinones - administration & dosage
Benzodiazepinones - pharmacology
Biological and medical sciences
Cancer Research
Cell Line, Tumor
Cell Proliferation - drug effects
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Disease Models, Animal
Female
Gastrins
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Nude
Oncology
Original Article
Pancreatic Neoplasms - drug therapy
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phosphorylation - drug effects
Proto-Oncogene Proteins c-akt - drug effects
Proto-Oncogene Proteins c-akt - metabolism
Receptor, Cholecystokinin B - antagonists & inhibitors
Survival Rate
Tumors
Xenograft Model Antitumor Assays
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Summary:Purpose Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [( R )-(−)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1 H -benzo[ b ][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines. Results Z-360 potently inhibited specific binding of [ 3 H]CCK-8 to the human CCK-2 receptor, with a K i value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P  
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-007-0591-8