devazepide and Pancreatic-Neoplasms

Pancreatic cancer is extremely resistant to various cancer therapies, however, variety of new therapies for pancreatic cancer have been investigated: (1) immunotherapy including cytokines like TNF, adoptive immunotherapy with lymphokine-activated killer cells or cytotoxic T-lymphocytes, and tumor vaccines using mutated Ki-ras oncoprotein or irradiated tumor cells which were transfected by cytokine genes; (2) gene therapy including transfer of cytokine genes or antisense Ki-ras oncogene, and a combination of gene transfer of herpes simplex virus thymidine kinase and subsequent administration of ganciclovir; (3) differentiation therapy including a quinolinone derivative, vesnarinone; (4) endocrine therapy including cholecystokinin-receptor antagonist, CR1505 or L364,718; (5) heavy water, and etc. All of these therapies will be applied for the treatment of pancreatic cancer in the near future.

Topics: Animals; Benzodiazepinones; Deuterium Oxide; Devazepide; Genetic Therapy; Humans; Immunotherapy; Pancreatic Neoplasms; Proglumide; Quinolones; Receptors, Cholecystokinin

MK-329 is a nonpeptidal, highly specific cholecystokinin (CCK) receptor antagonist, with affinity for pancreatic and gallbladder CCK receptors similar to CCK itself. MK-329 and its progenitor, asperlicin, can inhibit the growth of CCK receptor-positive human pancreatic cancer in athymic mice. Based on these activities and the ability of MK-329 to transiently increase food intake and enhance morphine analgesia in murine models, we conducted an open trial of MK-329 in 18 patients with advanced pancreatic cancer in whom the CCK receptor status of the tumors was unknown. Tumor response, pain control, and nutritional parameters (hunger rating, caloric intake, body weight, and anthropometrics) were serially assessed. The results of the study failed to demonstrate any impact of MK-329 on tumor progression, pain, or nutrition. Toxicity was mild and limited to nausea, vomiting, diarrhea, and abdominal cramps, with 17 of 18 patients able to tolerate treatment. While a role for MK-329 in the management of patients with advanced pancreatic cancer cannot be supported by the results of this trial, additional studies of this agent in patients with known CCK receptor-positive tumors, at escalated doses, and possibly in conjunction with other growth antagonists, appear warranted.

Topics: Adenocarcinoma; Adult; Aged; Analgesia; Benzodiazepinones; Cholecystokinin; Devazepide; Female; Humans; Male; Middle Aged; Nutritional Physiological Phenomena; Pancreatic Neoplasms; Receptors, Cholecystokinin

Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer. The incidence of pancreatic cancer is increased in countries that consume diets high in fat.. The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin (CCK) on pancreatic tumor growth and metastasis in an immunocompetent animal model.. C57BL/6 mice were placed on regular, low-fat, or high-fat diets for 8 weeks before establishment of Panc-02 orthotopic pancreatic tumors. Mice were then treated with a CCK-A receptor antagonist, devazepide, or vehicle for an additional 2.5 weeks. Pancreas tumors were weighed and metastases counted. Blood CCK levels were measured by radioimmunoassay (RIA). Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array. Effects of the CCK antagonist on Panc-02 cells invasiveness was assessed in a Matrigel invasion assay.. Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls (p < 0.01). Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls. The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A (VEGF-A) expression in tumors (p < 6 × 10(-9)). In vitro invasiveness of Panc-02 cells also was reduced by CCK-A receptor antagonist treatment (p = 1.33 × 10(-6)).. CCK is a mediator of dietary fat-associated pancreatic cancer. CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving VEGF-A.

Topics: Animals; Blood Glucose; Cell Line, Tumor; Cholecystokinin; Devazepide; Dietary Fats; Dose-Response Relationship, Drug; Embolism; Hormone Antagonists; Male; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Pancreatic Neoplasms; Radioimmunoassay

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

The peptide hormone cholecystokinin (CCK) plays an important role in the gastrointestinal tract. The rat pancreatic CCK receptor is a highly glycosylated membrane receptor that is able to bind to plant lectins such as wheat germ agglutinin (WGA) and Ulex europaeus agglutinin (UEA-I).. We used both lectins to block this receptor for studying the pathophysiologic relevance of its oligosaccharide side chains. In the present study we investigated the influence of WGA and UEA-I on CCK-8-induced alpha-amylase secretion of the rat pancreatic tumor cell line AR42J, which expresses both CCK-A and CCK-B receptors.. Under the influence of WGA (25 microg/mL), the alpha-amylase release was reduced by 25% after 30 minutes compared with the hormone-stimulated controls. UEA-I (25 microg/mL) caused a reduction of 20%. The simultaneous application of the lectins with CCK antagonists L 364,718 or L 365,260 led to a reduction of secretion, but the assignment to CCK-A or CCK-B receptors was not possible.. In long-term studies, both lectins revealed no toxic or apoptosis-inducing effects. On the contrary, WGA showed an inhibitory effect on cell proliferation and led to improved differentiation of cells.

Topics: alpha-Amylases; Animals; Benzodiazepinones; Cell Differentiation; Cell Division; Devazepide; Kinetics; Lectins; Microscopy, Electron; Pancreas; Pancreatic Neoplasms; Phenylurea Compounds; Plant Lectins; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Tumor Cells, Cultured; Wheat Germ Agglutinins

The role of cholecystokinin (CCK) and gastrin in the development and growth of pancreatic cancer cells is controversial. The aim of this study was to evaluate the role of CCK-8S, gastrin-17, bombesin, and their antagonists on cell lines from patients with pancreatic cancer.. Cell lines were established from pancreatic cancers operated on at our department. The cells were grown in 10% fetal calf serum (FCS). The effects of CCK-8S, gastrin-17, bombesin, and their antagonists in different concentrations and for different time intervals were studied. The cell number was evaluated with the XTT method.. The cell line LN 36 responded with increased cell number to stimulation by gastrin-17 and decreased cell number to inhibition by the CCK-B receptor antagonist L-365,260. In contrast, LPC 1 responded with increased cell number to CCK-8S and decreased cell number to the CCK-A receptor antagonist devazepide. LPC 2, 6, and 7 were stimulated by CCK-8S, gastrin-17, and their antagonists. LPC 3 showed decreased cell number after inhibition by the antagonists, and LPC 5 and 10 showed increased cell number after stimulation by CCK-8S and gastrin-17. LPC 4 was stimulated by CCK-8S, and LPC 8 was stimulated by all substances except gastrin-17. Intermittent administration of the substances to LN 36 led to a greater effect on the cell number than administration every day, which was not the case with LPC 1 and LPC 3. Bombesin led to an increased growth in LPC 5 but not in LPC 3.. CCK-8S and gastrin-17 led to an increased cell number in some cell lines. A blockade of the CCK-A and CCK-B receptors by their antagonists led to an increased, an unaffected, or a decreased cell number of the cell lines. The effect of bombesin on different cell lines also varied. This shows a great heterogenicity among pancreatic cancer cells from different patients.

Topics: Benzodiazepinones; Bombesin; Cell Division; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Gastrins; In Vitro Techniques; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin; Tumor Cells, Cultured

It was recently found that cholecystokinin (CCK) activates mitogen-activated protein kinases (MAPK) in isolated rat pancreatic acini. The present study evaluates whether one or both types of CCK receptors are capable of MAPK activation in pancreatic AR42J acinar cells as well as CHO cells transfected with CCK-A or CCK-B receptors. CCK significantly increased p44 MAPK and p42 MAPK activities in AR42J cells. Minimal, half-maximal, and maximal responses were observed at 30 and 500 pM and 10 nM, respectively, after CCK-8 stimulation and at 100 pM and 1.5 and 30 nM, respectively, after gastrin stimulation. Glycine-extended gastrin had no effect at 100 nM and a small but significant effect at 1 microM. The CCK-B receptor antagonist L365,260 almost totally blocked MAPK activation in AR42J cells after stimulation with gastrin and glycine-extended gastrin and substantially reduced the activation of both kinases by CCK-8, while the CCK-A receptor antagonist L364,718 was much less effective. The CCK-A-selective agonist A71376, however, was an effective stimulant of MAPK activity. In an alternative approach, stably transfected CHO cells bearing either CCK-A or CCK-B receptors were stimulated with CCK-8. Each receptor induced a time-dependent increase in activity of both MAPKs by five- to sixfold in CCK-A- and CCK-B-bearing cells. In conclusion, both CCK-A and CCK-B receptors activate MAPK in AR42J cells and in transfected CHO cells.

Topics: Animals; Benzodiazepinones; Blotting, Western; Carcinoma, Acinar Cell; Cells, Cultured; CHO Cells; Cricetinae; Devazepide; Dose-Response Relationship, Drug; Gastrins; MAP Kinase Kinase Kinase 4; MAP Kinase Kinase Kinases; Oligopeptides; Pancreatic Neoplasms; Phenylurea Compounds; Protein Kinases; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reference Values; Sincalide; Transfection; Tumor Cells, Cultured

The mechanism by which high-fat diets potentiate pancreatic cancer is not known, but pancreaticotrophic hormones such as cholecystokinin (CCK) may be involved. The effect of CCK receptor blockade on carcinogenesis during the entire promotion period was investigated in Syrian Golden hamsters fed a high- or low-fat diet and treated with N-nitrosobis(2-oxopropyl)amine (3 x 10 mg/kg at weekly intervals). One-half of the hamsters fed a high-fat diet received the CCK-A receptor antagonist devazepide (25 nmol/kg/hr) for the duration of the experiment. At 39 weeks the incidence of pancreatic malignancies was significantly higher in hamsters fed the high-fat diet than in those fed the low-fat diet (p < 0.05). Tumor incidence was not changed by CCK receptor blockade. Potentiation of pancreatic cancer by a high-fat diet in hamsters does not appear to be influenced by endogenous CCK during the tumor promotion period.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Devazepide; Dietary Fats; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Receptors, Cholecystokinin

The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L-365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor.

Topics: Animals; Benzodiazepinones; Cell Division; Cell Line; Cholecystokinin; Devazepide; Gastrins; Growth Substances; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Pentagastrin; Phenylurea Compounds; Receptors, Cholecystokinin; Transplantation, Heterologous; Tumor Cells, Cultured

Cholecystokinin (CCK) is an important trophic hormone for the pancreas, and CCK receptors are present on pancreatic carcinoma cells. We sought to determine whether either CCK itself or an antagonist of CCK could modulate the sensitivity of the human pancreatic cell line MIA-PaCa2 to cisplatin (DDP). The IC50 for a 1-h exposure to DDP was 35.3 +/- 3.2(SD) microM. Exposure to CCK8 octapeptide at physiologic and supra-physiologic concentrations did not alter the sensitivity of MIA-PaCa2 cells to DDP. The CCK receptor antagonist MK-329 was directly cytotoxic to the MIA-PaCa2 cells on a constant exposure schedule with an IC50 of 9.5 +/- 1.4 (SD) microM. MK-329 enhanced the sensitivity of MIA-PaCa2 cells to DDP by a factor of 3.5, and the interaction between DDP and MK-329 was shown to be synergistic by median-effect analysis. At a level of 50% cell kill, the combination index was 0.58 +/- 0.10. The ability of MK-329 to sensitize cells to DDP was schedule-dependent and required prolonged exposure to the antagonist following a 1-h exposure to DDP. MK-329 had no effect on the uptake of a radiolabeled analog of cisplatin ([3H]-dichloro(ethylenediamine)platinum) and did not affect intracellular glutathione content. MK-329 had no effect on the cell-cycle-phase distribution of MIA-PaCa2 cells and did not alter the DDP-induced cell-cycle perturbations. The cytotoxic effect of MK-329 and its ability to interact synergistically with DDP could not be reversed by CCK. We conclude that MK-329 is directly cytotoxic to pancreatic carcinoma cells and can enhance their sensitivity to DDP by a mechanism not related to its ability to antagonize the CCK receptor.

Topics: Antineoplastic Agents; Benzodiazepinones; Cell Cycle; Cholecystokinin; Cisplatin; Devazepide; Dose-Response Relationship, Drug; Drug Synergism; Humans; Organoplatinum Compounds; Pancreatic Neoplasms; Time Factors; Tumor Cells, Cultured

The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Devazepide; Diet; Dietary Fats; DNA; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Receptors, Cholecystokinin; RNA

Cholecystokinin (CCK) exerts an influential effect on the growth of normal pancreas. It is postulated that carcinoma arising from the pancreas may retain some normal pancreatic properties as far as hormone dependency is concerned. In an effort to examine the effect of CCK on the growth of pancreatic cancer, we evaluated the effect of CCK receptor antagonist on the growth of a transplantable adenocarcinoma of the pancreas. For this study we utilized three groups of hamsters with adenocarcinoma of the pancreas transplanted subcutaneously on the right flank. Group I (n = 15) served as control. Group II (n = 15) received CCK receptor antagonist (L-364,718), 0.1 mg/100 g body wt subcutaneously BID. Group III received CCK receptor antagonist in the same dose but treatment was started after tumors became palpable. All animals were examined daily. Latency for tumor growth, tumor size, and body weight were recorded. Animals were sacrificed after 3 weeks and final tumor volume and weight were measured. CCK receptor antagonist (L-364,718) significantly reduced pancreatic carcinoma growth when given immediately after transplantation and also in animals with established tumor. However, this inhibitory effect of L-364,718 was only partial and effective only for a brief time. This finding suggests CCK may have only a minimal influence on the biologic behavior of exocrine pancreatic cancer.

Topics: Adenocarcinoma; Animals; Benzodiazepinones; Cricetinae; Devazepide; Male; Mesocricetus; Neoplasm Transplantation; Pancreas; Pancreatic Neoplasms; Receptors, Cholecystokinin; Sincalide; Succinimides

The effects of a high-fat diet and the CCK-receptor antagonist, L364,718, were examined on growth of human pancreas cell line SW-1990 xenografted to nude mice. Sixty animals were fed either low-fat (4.3%) or high-fat (20.25%) diet. Fifteen mice in each diet group were treated with L364,718 (2 mg/kg) subcutaneously twice daily for 23 days. On day 24 the animals were sacrificed. Tumor and animal pancreases were dissected and evaluated for weight, protein, and DNA content. When comparing within each diet group, L364,718 significantly decreased tumor volume, weight, protein, and DNA content compared to untreated mice (P less than 0.005). Tumor volume and protein content were significantly larger in untreated animals on the high-fat diet (P less than 0.05) compared to the low-fat diet. Mouse pancreatic weight, protein, and DNA content per kilogram of animal weight were all significantly lower (P less than 0.005) in mice on the low-fat diet treated with L364,718. Pancreatic DNA content was also decreased in both groups of animals on the high-fat diet compared to untreated mice on the low-fat diet. These findings suggest that diets high in unsaturated fat promote the growth of human pancreatic cancer. Since both tumor and pancreas growth are inhibited by the specific CCK-antagonist, L364,718, it is possible that endogenous CCK promotes the growth.

Topics: Animals; Benzodiazepinones; Devazepide; Dietary Fats; DNA; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Organ Size; Pancreas; Pancreatic Neoplasms; Transplantation, Heterologous