z-360 and Pancreatic-Neoplasms

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Disease Models, Animal; Drug Design; Gastric Acid; Gastrins; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms

We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer.. Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m. The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated.. In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Deoxycytidine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gemcitabine; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Receptor, Cholecystokinin B; Survival Rate

To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer.. Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded.. Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain.. Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Deoxycytidine; Female; Gastrins; Gemcitabine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Quality of Life; Receptor, Cholecystokinin B; Severity of Illness Index; Survival Analysis; Treatment Outcome

The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model.. The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity.. In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect.. These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.

Topics: Animals; Apoptosis; Benzodiazepinones; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Endopeptidases; Gastrins; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Pancreatic Neoplasms; Receptor, Cholecystokinin B; Survivin; X-Linked Inhibitor of Apoptosis Protein; Xenograft Model Antitumor Assays

As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells.. In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA.. Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360.. Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy.

Topics: Antimetabolites, Antineoplastic; Benzodiazepinones; Cell Line, Tumor; Deoxycytidine; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Isoforms; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Receptor, Cholecystokinin B; Signal Transduction; Vascular Endothelial Growth Factor A

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.

Topics: Animals; Benzodiazepinones; Cell Line, Tumor; Deoxycytidine; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Mice; Pancreatic Neoplasms; Receptor, Cholecystokinin B; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production.. In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region.. We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

Topics: Animals; Benzodiazepinones; Cell Line, Tumor; Devazepide; Disease Models, Animal; Ephrin-B1; Extremities; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Injections; Interleukin-1beta; Mice; Pain; Pancreatic Neoplasms; Phosphorylation; Receptors, Eph Family; Receptors, N-Methyl-D-Aspartate; Sincalide; Up-Regulation

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.. 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.. 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.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Female; Gastrins; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Survival Rate; Xenograft Model Antitumor Assays