peptide-phi and Pancreatic-Neoplasms

Topics: Adenoma, Islet Cell; Ganglioneuroma; Humans; Pancreatic Neoplasms; Peptide PHI; Protein Precursors; Vasoactive Intestinal Peptide; Vipoma

Topics: Amino Acid Sequence; Animals; Base Sequence; Digestive System Physiological Phenomena; DNA; Glucagon; Growth Hormone-Releasing Hormone; Humans; Hypothalamus; Median Eminence; Pancreatic Neoplasms; Peptide PHI; Peptides; Pituitary Gland; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Secretin; Swine; Tissue Distribution; Vasoactive Intestinal Peptide

Specific binding sites for 125I-labelled rat peptide-histidine-isoleucine (PHI) were identified on rat insulinoma-derived RINm5F cells. The concentrations of peptides producing half-maximal displacement of label were rat PHI, 0.36 +/- 0.14 nM, vasoactive intestinal polypeptide (VIP), 0.38 +/- 0.13 nM and secretin, approximately 0.2 microM. Glucagon and glucagon-like peptide-1(7-36)amide were without effect on binding. PHI and VIP produced dose-dependent increases in cAMP production in the cells that were significantly (P less than 0.05) above unstimulated rates for ligand concentrations between 10(-8) and 10(-6) M. Both PHI and VIP produced a small but significant (P less than 0.05) enhancement in the rate of release of immunoreactive insulin from the cells but the effect was not dose dependent.

Topics: Adenoma, Islet Cell; Adenylyl Cyclases; Animals; Cyclic AMP; Enzyme Activation; Insulin; Insulin Secretion; Insulinoma; Iodine Radioisotopes; Pancreatic Neoplasms; Peptide PHI; Rats; Receptors, Cell Surface; Receptors, Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The presence of peptide histidine-methionine (PHM)-like peptides has been determined in plasma and tumor specimens from patients with vasoactive intestinal peptide (VIP)-secreting tumors and the watery diarrhea syndrome. All patients had strikingly elevated plasma concentrations of PHM immunoreactivity (median, 1800; range, 500-6800 pmol/liter; n = 12), which were higher than those of VIP (median, 235; range, 50-580 pmol/liter). In patients with other endocrine and nonendocrine pancreatic tumors, plasma PHM concentrations were not significantly different from normal (median, 20; range, 5-60 pmol/liter; n = 28). Plasma samples from patients with diarrhea due to other illnesses also had PHM concentrations that were not significantly different from normal (median, 40; range, 10-80 pmol/liter; n = 23). The gel chromatographic profiles of plasma and tumor extracts from patients with VIP-secreting tumors revealed the presence of at least two molecular forms that reacted with an antiserum directed to the N-terminus of PHM (SY1). The later peak (Kav, 0.50-0.53) corresponded in position to synthetic PHM and also reacted with the PHM-specific antiserum (SY2). The earlier peak (Kav, 0.30-0.37), not reactive with antiserum SY2, corresponded to a large molecular form of PHM-like immunoreactivity previously identified as the predominant form in normal human stomach and plasma, though not in the rest of the intestinal tract. The neuroendocrine nature of the tumors was confirmed by the demonstration of immunostaining with a battery of antisera to neuroendocrine markers. Immunocytochemistry revealed the presence of both VIP and PHM in tumor cells. The presence of high circulating concentrations of PHM-like immunoreactivity in patients with VIP-secreting tumors, as measured with a PHM N-terminus-directed antiserum, SY1, suggests that use of this type of antiserum may provide valuable information in the diagnosis of such tumors. The contribution of the PHM-like peptides to the features of this syndrome is not known.

Topics: Adenoma, Islet Cell; Antibodies; Chromatography, Gel; Histocytochemistry; Humans; Immune Sera; Immunoenzyme Techniques; Pancreatic Neoplasms; Peptide PHI; Radioimmunoassay; Vasoactive Intestinal Peptide; Vipoma

Using regional specific antisera the concentrations of vasoactive intestinal polypeptide (VIP) and the peptide with N-terminal histidine and C-terminal isoleucine (PHI) in various peripheral tissues and VIP producing tumours were compared with their immunohistochemical localization. In normal tissue the VIP levels were in general higher than the PHI levels, while the VIP/PHI ratio in tumour tissue varied considerably more than in normal tissue. By immunohistochemistry it was found that VIP and PHI immunoreactivity occurred in the same autonomic neurons. Gel chromatography revealed that VIP and PHI immunoreactivity in both normal and tumour tissue consisted of two larger molecular forms in addition to "authentic" peptides. These larger molecular forms which had overlapping elution positions probably represent VIP/PHI precursors. In tumour tissue the larger molecular forms constituted a larger proportion of the total immunoreactivity. Neurally induced relaxation of smooth muscle caused a simultaneous release of VIP and PHI which in combination with the observed relaxatory effect of the peptide suggest a role in the control of smooth muscle activity. Similarly VIP and PHI were co-secreted from tumour tissues as evidenced from elevated plasma levels in patients with VIP producing tumours. In conclusion VIP and PHI seem to co-exist and be co-secreted. Differences in posttranslational processing may create variable content and release of the two peptides.

Topics: Animals; Cats; Digestive System; Ganglioneuroma; Humans; Neuroblastoma; Pancreatic Neoplasms; Peptide PHI; Reference Values; Species Specificity; Swine; Tissue Distribution; Vasoactive Intestinal Peptide

VIP and secretin control the secretory function of the normal pancreas. We analysed their regulatory functions in a human pancreatic cancer cell line: Capan-1. Saturation binding experiments with 125I-VIP showed the existence of one class of binding sites of very high affinity: KD 6.4 +/- 3.0 X 10(-11) M and a low Bmax: 12 fmoles/10(6) cells, in both intact cells and membrane preparations. This site has not yet been described in normal or tumorous digestive cells. Competition binding experiments let us characterize two more binding sites, KD: 2.1 +/- 0.7 X 10(-9) M and 5.0 +/- 0.6 X 10(-8) M and the corresponding Bmax: 120 and 500 fmoles/10(6) cells. These sites are similar to those found on cells of the digestive tract. Competition binding experiments gave the following IC50: 3.0 +/- 0.9 X 10(-9) M for VIP; 2 +/- 0.6 X 10(-6) M for PHI; and 1 +/- 0.7 X 10(-5) M for secretin. VIP elicited a cAMP rise, the half maximal response being obtained at 1.2 X 10(-10) M. Secretin induced a cAMP response but only for concentrations higher than 10(-8) M. VIP receptors were found to be modulated by two factors: cell ageing and cell density. Cells chronically treated with VIP showed a slight decrease of their proliferation; insulin exerted an opposite effect. It is concluded that at the difference of normal pancreatic cells, the present cell line lacks secretin-preferring receptors and acquires some of the properties of intestinal cells.

Topics: Binding, Competitive; Cell Division; Cell Line; Cell Membrane; Cyclic AMP; Humans; Kinetics; Pancreatic Neoplasms; Peptide PHI; Peptides; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Secretin; Vasoactive Intestinal Peptide

Nine pancreatic endocrine tumours of patients with watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome were examined by immunohistochemistry and electron microscopy. All cases revealed neoplastic proliferation of VIP (vasoactive intestinal peptide)-immunoreactive (IR) cells. Immunoreactivity to a novel peptide hormone PHM-27, which is processed from a common big precursor peptide of VIP (prepro VIP/PHM-27), was identified in VIP-IR cells of 8 tumours. VIP-PHM-IR cells had secretory granules measuring about 130 to 220 nm in diameter. Radioimmunoassay of tumour tissue extracts showed high VIP and PHM contents in proportional amounts in most cases. According to the results of immunostaining, the 8 tumours fell into two large groups; 5 with PP (pancreatic polypeptide)-IR cells and 3 with CT (calcitonin)-IR cells. The former group demonstrated VIP cells and PP cells intermingled in various proportions, including one tumour in which coexistence of PP-IR and VIP-IR in the same cells was demonstrated. Cell heterogeneity of the tumours and possible relationships of VIP, PP and CT cells were discussed.

Topics: Adenoma, Islet Cell; Calcitonin; Histocytochemistry; Humans; Immunochemistry; Microscopy, Electron; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Peptide PHI; Protein Precursors; Radioimmunoassay; Staining and Labeling; Vasoactive Intestinal Peptide; Vipoma

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.

Topics: Adult; Aged; Diarrhea; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptide PHI; Peptides; Somatostatin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adult; Aged; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptide PHI; Peptides; Protein Precursors; Vasoactive Intestinal Peptide; Vipoma

Peptide histidine isoleucine (PHI), first isolated from pig intestine, is distributed identically to vasoactive intestinal peptide (VIP) in all mammals. 42 patients with high plasma VIP secondary to VIPoma also had very high plasma PHI-like immunoreactivity, in a constant ratio to VIP. None of 125 patients with other endocrine tumours had high levels of either peptide. VIPoma tissue from 20 patients also contained PHI shown by immunocytochemistry to be produced by the same cell as VIP. Messenger RNA(mRNA) from one of these tumours contained the codes for VIP and a separate PHI-like sequence. Human PHI-like sequence differed from porcine PHI in only two aminoacid residues. A single cell thus produces two separate regulatory peptides with apparently similar potencies but different spectra of activity. In normal tissue the constant coproduction of two active neuropeptides by a single neuron provides further evidence against the doctrine of one neuron producing only one neurotransmitter.

Topics: Adenoma, Islet Cell; Base Sequence; Diarrhea; Genetic Code; Histocytochemistry; Humans; Intestinal Secretions; Intestine, Small; Pancreatic Neoplasms; Peptide PHI; Peptides; Radioimmunoassay; RNA, Messenger; RNA, Neoplasm; Vasoactive Intestinal Peptide; Vipoma