cholecystokinin and Carcinoma--Intraductal--Noninfiltrating

Topics: Abdomen; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Diabetes Mellitus; Hepatomegaly; Humans; Jaundice; Laparotomy; Mental Disorders; Pain; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Prednisolone; Prognosis; Radioisotopes; Radionuclide Imaging; Secretin; Selenium

The effects of cholecystokinin (CCK) and a CCK antagonist, loxiglumide (CR-1505), on four freshly separated and six xenografted human pancreatic cancers, were investigated. The level of DNA synthesis in only one of five tested pancreatic cancers was enhanced by CCK at concentrations of 0.01-10 nM, while in the other four cancers DNA synthesis was not affected. The levels of DNA, RNA, and protein synthesis (by 3H-thymidine, 3H-uridine, and 3H-leucine incorporation tests, respectively) in all the tested cancers were dose-dependently inhibited by loxiglumide at concentrations of 20-2000 microM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 microM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted line (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of loxiglumide for nude mice was about 500 mg/kg. Death was caused by respiratory failure due to severe congestion of the lung after the administration of a large dose of loxiglumide. The growth of a PC-HN transplanted in the nude mice was significantly inhibited by subcutaneous loxiglumide at 250 mg/kg, twice a day for 28 days, which did not cause death. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its action as a CCK antagonist, and this study also suggests that loxiglumide may be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.

Topics: Animals; Carcinoma, Intraductal, Noninfiltrating; Cholecystokinin; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Proglumide; RNA, Neoplasm; Transplantation, Heterologous; Tumor Cells, Cultured

To examine the effect of cholecystokinin (CCK) on pancreatic carcinogenicity in the hamster model, two sets of experiments were carried out. In one study, CCK (20 IDU/kg body wt) was given 3 h before, simultaneously with or 3 h after a single dose (20 mg/kg body wt) of N-nitrosobis(2-oxopropyl)amine (BOP). In another experiment, hamsters were treated similarly except that both CCK (20 IDU/kg body wt) and BOP (2.5 mg/kg body wt) were given weekly for 20 weeks. The results showed that CCK in the first experiment (single BOP dose) inhibited pancreatic cancer induction in a statistically significant fashion when given either 3 h prior to (P less than 0.05) or simultaneously with BOP (P less than 0.0005); however, CCK, when administered after BOP did not alter the cancer incidence as compared with hamsters treated with BOP alone. In the second experiment (chronic BOP treatment) the pattern and the incidence of pancreatic tumors were not affected by CCK.

Topics: Adenoma; Animals; Carcinogens; Carcinoma, Intraductal, Noninfiltrating; Cholecystokinin; Cricetinae; Female; Male; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms

Plasma concentrations of human pancreatic polypeptide (HPP) parallel exocrine pancreatic secretion in response to stimulation with cholecystokinin. We determined prospectively the relationships among fasting HPP level, integrated HPP response to infusion of cholecystokinin, and output of trypsin and also the sensitivity, specificity, and predictive values of the fasting HPP level in the diagnosis of exocrine pancreatic disease. Our study group consisted of 19 patients with acute pancreatitis, 17 with chronic pancreatitis, and 25 with ductal adenocarcinoma of the pancreas and 27 control subjects. In the control patients and those with chronic pancreatitis, significant correlations were detected between HPP level and output of trypsin (P less than 0.001) in response to infusion of cholecystokinin and between fasting HPP and integrated HPP levels (P less than 0.004); no correlation was detected between HPP level and steatorrhea. The sensitivity, specificity, and negative and positive predictive values of the fasting HPP level for detection of either chronic pancreatitis or pancreatic cancer were similar and approximated 0.88, 0.67, 0.88, and 0.66, respectively. The HPP concentration had no value in detecting acute pancreatitis. Because the fasting HPP level has a high degree of negative predictability and is simpler to measure than the integrated HPP level or the output of trypsin, it may be a useful test in patients suspected of having either chronic pancreatitis or pancreatic cancer. A fasting HPP level of 125 pg/ml or greater could be used to exclude chronic pancreatitis or pancreatic cancer, but the finding of a value of less than 125 pg/ml necessitates use of other diagnostic tests for reliable determination of the presence of these diseases.

Topics: Acute Disease; Adult; Aged; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Chronic Disease; Fasting; Humans; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatic Polypeptide; Pancreatitis; Prospective Studies; Trypsin