NON-GASTRIN ACID SECRETAGOGUE IN ISLET CELL TUMORS
Principal Investigator: William Chey
Abstract: In a group of patients with pancreatic islet cell neoplasms, marked gastric acid hypersecretion and peptic ulceration and/or diarrhea, normal plasma concentrations of gastrin were found. In both pancreatic neoplasms and plasmas of these patients we found a non-gastrin acid secretagogue (NGAS) activity which appears to be due to a group of trypsin-sensitive and acidic peptides that are not cross-reactive to our antigastrin serum. Long-term objectives are 1) to identify this NGAS by radioimmunoassay (RIA) in these patients for early diagnosis, and 2) to study physiology, pharmacology and pathophysiology of NGAS. The specific aims of the present proposal are 1) purification to homogeneity of NGAS from the tumor extract and porcine intestinal extract (since similar secretagogues were found in porcine intestinal extracts), 2) amino acid sequence determination and chemical synthesis of NGAS, 3) its biological characterization and 4) development of RIA of NGAS. Peptides with NGAS activity will be purified from both tumor and intestinal extracts. Initially, a peptide of NGAS activity will be purified from a Sephadex G-25 fraction of "cholecystokinin CM-cellulose side fraction (CCK-CMC-I)" of intestinal extract by reverse-phase high performance liquid chromatography (HPLC) on a semi-preparative C18 column followed by HPLC on an analytical C18 column and rechromatography. Once purified, its primary structure will be determined and synthetic peptide will be prepared. A specific RIA will be developed to detect any cross-reactive substances in both tumor extract and CCK CMC-I fractions. The cross-reactive substances in both will then be purified according to the developed methods. The amino acid sequence of the tumor NGAS will be determined and compared with those purified from intestinal extract to make sure that they have sequence homology and thus belong to the same family of peptides. When synthetic NGAS will be available, its secretagogue activity will be tested in rats and conscious dogs with gastric cannulas and fundic pouches and will be compared with pure natural NGAS. The potency of NGAS will be compared also with hG-17I. The interaction between NGAS and other secretagogues including hG-17I and histamine will be studied in both rats and dogs and using isolated parietal cell preparations of rabbits and dogs. Immunoreactive NGAS will be determined in plasmas of patients with ulcerogenic tumor syndrome, patients with duodenal ulcer disease and normal human subjects. Immunoreactive NGAS contents will be determined in islet cell tumors also. Finally, release of NGAS in response to a meat meal will be studied in dogs.
Funding Period: 1988-08-01 - 1991-07-31
more information: NIH RePORT