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.

Abstract

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-1H-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 [3H]CCK-8 to the human CCK-2 receptor, with a Ki 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<0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P<0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P<0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls.

CONCLUSION:

In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.

• Authors: Daisuke Kawasaki, Yutaka Emori, Runa Eta, Yuka Iino, Hiroki Hamano, Koji Yoshinaga, Takao Tanaka, Mineo Takei, Susan A Watson
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 61 Issue 5 Pg. 883-92 (Apr 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17901954 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzodiazepinones
• Gastrins
• Receptor, Cholecystokinin B
• Z-360
• Deoxycytidine
• gastrin 17
• Proto-Oncogene Proteins c-akt
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy)
• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzodiazepinones (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Disease Models, Animal
• Female
• Gastrins
• Humans
• Mice
• Mice, Nude
• Pancreatic Neoplasms (drug therapy)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (drug effects, metabolism)
• Receptor, Cholecystokinin B (antagonists & inhibitors)
• Survival Rate
• Xenograft Model Antitumor Assays
• Gemcitabine