vasoactive-intestinal-peptide and Lung-Neoplasms

Vasoactive intestinal peptide (VIP) is a neuropeptide of multiple functions affecting development and aging. In cancer, for example, VIP was found to function as an autocrine growth factor in nonsmall cell lung cancer (NSCLC) promotion. Furthermore, a VIP hybrid antagonist (neurotensin(6-11)-VIP(7-28)) was found to inhibit NSCLC growth. In the present study, the expression of VIP mRNA was studied using human lung cancer cells. RNA prepared from 19 cell lines was fractionated by 1% agarose gel electrophoresis followed by blotting onto nitrocellulose membranes and hybridization to a VIP-specific RNA probe. VIP mRNA was detected in about 50% of the cell lines tested with a greater abundance in NSCLC. Cultures of the NSCLC NCI-H727 cell line were treated with forskolin, an activator of cyclic AMP (cAMP), and separately with the tumor promoter phorbol 12-myristate 13-acetate (PMA). Northern blot hybridization analysis showed an increase in VIP mRNA levels after 4 h treatment with 50 microM forskolin. Incubation with PMA also showed a significant increase in the levels of VIP transcripts. Cultures were then incubated with PMA in the presence of actinomycin D, a transcription blocker. Results indicated that PMA treatment may induce both VIP mRNA synthesis as well as VIP mRNA stabilization, and suggested a 4-5 h half-life for the VIP mRNA in the absence of PMA. Thus, lung cancer tumor proliferation may be regulated, in part, at the level of VIP gene expression.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Colforsin; Cyclic AMP; Dactinomycin; Female; Gene Expression Regulation; Humans; Lung Neoplasms; Male; Neoplasm Proteins; Neurosecretory Systems; Nucleic Acid Synthesis Inhibitors; Organ Specificity; Rats; RNA, Messenger; RNA, Neoplasm; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Topics: alpha-Fetoproteins; Amines; Animals; Bombesin; Bronchi; Calcitonin; Calmodulin; Carcinoembryonic Antigen; Carcinoma in Situ; Carcinoma, Bronchogenic; Chorionic Gonadotropin; Cytoskeletal Proteins; Esophageal Neoplasms; Glycogen; Growth Hormone; Hormones; Humans; Intestinal Neoplasms; Lung Neoplasms; Parathyroid Hormone; Physalaemin; Placental Lactogen; Precancerous Conditions; Somatostatin; Vasoactive Intestinal Peptide

Lung adenocarcinoma is the most frequent form of non-small cell lung cancer. Inside the tumor mass, uncontrolled cell proliferation generates hypoxic areas leading to activation of hypoxia-inducible factors (HIFs) responsible for neovascularization and tumor metastasis. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuropeptides widely distributed in respiratory organs. Previous studies have demonstrated that these peptides interfere with hypoxic pathways in various diseases, including tumors. However, their modulatory role in HIFs expression in lung adenocarcinomas has not yet been evaluated. In the present paper, we detected the expression profile of PACAP, VIP and related receptors in healthy and adenocarcinoma human lung tissue. To characterize peptides' modulatory effects on HIFs expression, we also exposed A549 lung adenocarcinoma cells and human normal bronchial epithelial BEAS-2B cells to microenvironmental hypoxia by treating them with deferoxamine (DFX). The results showed that PACAP and VIP significantly reduced HIF-1α and HIF-2α levels in both cell lines following hypoxic stress. The HIF-3α expression profile was related to cellular phenotype as it was lower in BEAS-2B and higher in A549 cells under low oxygen tension. In lung adenocarcinoma cells, peptide treatment restored HIF-3 α expression to control levels. These results suggest that endogenous PACAP and VIP exert controversial roles in cellular hypoxic microenvironments depending on the pathophysiological conditions of the lung tissue.

Topics: A549 Cells; Adenocarcinoma of Lung; Cell Line; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Tumor Microenvironment; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is one of the most plentiful neuropeptides in the lung and it has anti-inflammatory effects in the respiratory system. Triggering receptors expressed on myeloid cells-1 (TREM-1) and triggering receptors expressed on myeloid cells-2 (TREM-2) regulate immune responses to lipopolysaccharide (LPS). In the present study, we tested the expressions of TREM-1 and TREM-2 in various pulmonary cell lines and/or tissue using an animal model of LPS-induced acute lung injury (ALI), and determined the effects of VIP on expression of the TREM-1 and TREM-2 in lung tissues and cells from ALI mice. We found 1) expression of the TREM-1 mRNA from lung tissues of ALI was significantly increased, whereas the expression of TREM-2 mRNA was decreased in these tissues; 2) TREM-1 mRNA was only expressed in macrophages, while TREM-2 mRNA was detected in HBECs, lung fibroblasts, lung adenocarcinoma cells and macrophages; 3) the ratio of TREM-1 mRNA to TREM-2 mRNA was increased in LPS-induced lung tissues and macrophages; 4) VIP inhibited expression of the TREM-1 mRNA in a time- and dose-dependent manner in lung cells from LPS-induced ALI mice; however, it increased expression of the TREM-2 mRNA. As a result of these effects, VIP normalized the ratio of TREM-1 to TREM-2 mRNA in these cells. Our results suggest that VIP might exert its anti-inflammatory effect through a mechanism involved in regulation of expression of the TREM-1 and TREM-2 in LPS-induced ALI.

Topics: Acute Lung Injury; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Lung; Lung Neoplasms; Male; Membrane Glycoproteins; Mice; Myeloid Cells; Neoplasms; Neuroprotective Agents; Receptors, Immunologic; RNA, Messenger; Triggering Receptor Expressed on Myeloid Cells-1; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) binds to two receptors, VPAC1 and VPAC2. Non-selective VIP antagonists have been shown to inhibit human cancer cell proliferation and reduce tumor growth in mice. Many human cancers over-express VPAC1 but not VPAC2. We show that VPAC1-selective antagonists can inhibit human cancer cell proliferation and identify five positions in the VPAC1-selective antagonist PG 97-269 that may be responsible for VPAC1 selectivity. Position 16 appears to be particularly critical for selectivity, as demonstrated in the replacement of Arg16 of PG 97-269 with the native VIP amino acid; this single change results in greatly reduced VPAC1 binding and selectivity. Finally, we show that site-specific conjugation with a 22kDa polyethylene glycol (PEG) at the C-terminus of VPAC1-selective antagonists further improves VPAC1-selective binding and has minimal effect on antagonistic activity. Our studies have further solidified VPAC1 as a cancer target and offer the possibility of generating highly potent VPAC1-selective antagonists with minimal number of mutations to reduce the risk of immunogenicity and potentially prolonged duration of action to allow more efficient treatment regimen.

Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Electrophoresis, Polyacrylamide Gel; Humans; Lung Neoplasms; Molecular Sequence Data; Peptide Fragments; Polyethylene Glycols; Protein Binding; Radioimmunoassay; Receptors, Vasoactive Intestinal Polypeptide, Type I; Sequence Homology, Amino Acid; Structure-Activity Relationship; Vasoactive Intestinal Peptide

Verner-Morrison syndrome, characterized by diarrhea, hypokalemia, and hypochlorhydria, is caused most commonly by vasoactive intestinal polypeptide-secreting islet cell tumors of the pancreas. Verner-Morrison syndrome has not been described as a paraneoplastic syndrome in non-small cell lung cancer. We describe a 38-year-old man with metastatic non-small cell lung cancer of large cell carcinoma with neuroendocrine differentiation who presented with bone metastasis and intractable secretory diarrhea that was unresponsive to pharmacological treatment, including octreotide. Laboratory evaluation indicated elevated serum calcitonin and vasoactive intestinal polypeptide levels. Chemotherapy resulted in a transient response in the patient's diarrhea and neuroendocrine markers. The patient did not respond to further therapy and died 5 months after onset of back pain. To our knowledge, this is the first published case of large cell carcinoma with neuroendocrine differentiation associated with treatment-responsive paraneoplastic Verner-Morrison syndrome.

Topics: Adult; Calcitonin; Carcinoma, Large Cell; Humans; Lung Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Vasoactive Intestinal Peptide; Vipoma

The mechanism by which vasoactive intestinal peptide (VIP)-ellipticine (E) conjugates are cytotoxic for human lung cancer cells was investigated. VIP-alanyl-leucyl-alanyl-leucyl-alanine (ALALA)-E and VIP-leucyl-alanyl-leucyl-alanine (LALA)-E inhibited (125)I-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 microM, respectively. VIP-ALALA-E and VIP-LALA-E caused elevation of cAMP in NCI-H1299 cells with ED50 values of 0.7 and 0.1 microM. Radiolabeled VIP-LALA-E was internalized at 37 degrees C and delivered the cytotoxic E into NCI-H1299 cells. VIP-LALA-E inhibited the growth of NCI-H1299 cells in vitro. Three days after the addition of VIP-LALA-E to NCI-H1299 cells, cell viability decreased based on trypan blue exclusion and reduced 3H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC1 receptor-mediated endocytosis.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Drug Design; Ellipticines; Endocytosis; Humans; Lung Neoplasms; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; Thymidine; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is one of several small neuropeptides that affect cancer growth. A lipophilic VIP analog, stearyl-Nle(17)-neuroten-sin(6-11)VIP(7-28) (SNH) that inhibited lung carcinoma growth has been described previously. The experiments performed were clonogenic assays in vitro and tumor xenografts in nude mice in vivo. These studies were now extended to colon carcinoma and to combination therapy with chemotherapeutic agents.. Assays were performed with cell lines, and tumor proliferation was assessed using the (3-[4,5-dimethylthiazol-2-yl-5]-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium) (MTS) colorimetric assay for mitochondrial function of living cells.. The lipophilic analog (SNH) enhanced the antiproliferative activity of diverse chemotherapeutic agents: doxorubicine (antibiotic); vinorelbine (vinca alkaloid, antimicrotubule formation); paclitaxel (antimicrotubule agent); gemcitabine (antimetabolite); irinotecan (topoisomerase I inhibitor); and cisplatin (platinum compound acting as an alkylating agent). In all cases, the antiproliferative effect of SNH and the chemotheraputic agent was at least additive and for some combinations and concentrations even synergistic. For example, 2 microM of the antagonist that produced a 15-20% growth inhibition in the nonsmall cell lung carcinoma cell line reduced the IC(50) by 2-4-fold for most of the chemotherapeutic agents tested. Higher analog concentrations were even more efficacious. Similar results were obtained with colon carcinoma cell lines.. Chemotherapeutic treatment of advanced solid tumors, such as nonsmall cell lung carcinoma, colon carcinoma, or prostate carcinoma, achieves a response rate of between 10% and 30% with significant toxicity. Combination therapy with the lipophilic VIP analog SNH and the preferred chemotherapeutic agent may greatly enhance the response rate, and by permitting a dose reduction, should significantly reduce side effects.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Synergism; Growth Inhibitors; Humans; Lung Neoplasms; Neurotensin; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Tumor Stem Cell Assay; Vasoactive Intestinal Peptide; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents, Hormonal; Carcinoma, Small Cell; Cyclic AMP; Growth Hormone-Releasing Hormone; Humans; Lung Neoplasms; Mice; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

VIP/PACAP are autocrine growth factors for lung cancer. VIP and/or PACAP mRNA is present in most lung cancer cell lines examined. Although mRNA for VPAC2-R is not common, VPAC1-R and PAC1-R mRNA is present in many lung cancer cell lines. 125I-VIP binds with high affinity to lung cancer cells and specific 125I-VIP binding is inhibited with high affinity by (Lys15, Arg16, Leu27)VIP1-7 GRF8-27, the VPAC1-R specific agonist, but not by Ro25-1553(18), the VPAC2-R specific agonist. VIP elevates cAMP and increases c-fos gene expression. The increase in cAMP and c-fos mRNA caused by VIP is inhibited by SN(VH). (SH)VH inhibited the proliferation of NCIH1299 cells in the MTT assay, which is based on cytotoxicity. In a recent cell line screen, (SN)VH inhibited the growth of 51 of 56 cancer cell lines including leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, breast cancer, and prostate cancer (T. Moody, unpublished). It remains to be determined if (SN)VH will be useful for treatment of a wide variety of cancers.

Topics: Adenylyl Cyclases; Base Sequence; Female; Humans; Lung Neoplasms; Male; Neuropeptides; Oncogenes; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Pituitary Hormone; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Small-cell lung carcinoma (SCLC) is an aggressive, rapidly growing and metastasizing, and highly fatal neoplasm. We report that vasoactive intestinal peptide inhibits the proliferation of SCLC cells in culture and dramatically suppresses the growth of SCLC tumor-cell implants in athymic nude mice. In both cases, the inhibition was mediated apparently by a cAMP-dependent mechanism, because the inhibition was enhanced by the adenylate cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in proportion to increases in intracellular cAMP levels, and the inhibition was abolished by selective inhibition of cAMP-dependent protein kinase. If confirmed in clinical trials, this antiproliferative action of vasoactive intestinal peptide may offer a new and promising means of suppressing SCLC in human subjects, without the toxic side effects of chemotherapeutic agents.

Topics: 1-Methyl-3-isobutylxanthine; Adenylyl Cyclases; Animals; Carcinoma, Small Cell; Cell Division; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Humans; Lung Neoplasms; Mice; Mice, Nude; Phosphodiesterase Inhibitors; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The effects of VIP receptor antagonists were investigated using non-small cell lung cancer (NSCLC) cells. By Northern blot and RT-PCR, VIP1 receptors were detected on NSCLC cell line NCI-H1299. VIPhybrid,(N-Stearyl-Norleucine17) VIPhybrid ((SN) VIPhybrid) and PTC4495 inhibited 125I-VIP binding to NCI-H1299 cells with IC50 values of 500, 30 and 5000 nM respectively. (SN) VIPhybrid (1 microM) had no effect on basal cAMP but strongly inhibited the increase in cAMP caused by 10 nM VIP. The order of peptide potency to inhibit cAMP was (SN) VIPhybrid > VIPhybrid > PTC4495. (SN) VIPhybrid was more potent than VIPhybrid at inhibiting NCI-H1299 colony formation. Also, (SN) VIPhybrid was more potent than VIPhybrid at inhibiting NCI-H1299 xenograft formation in nude mice. These data suggest that (SN) VIPhybrid antagonizes VIP1 receptors on NSCLC cells.

Topics: Amino Acid Sequence; Animals; Carcinoma, Non-Small-Cell Lung; Cell Division; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The effects of PACAP on c-fos mRNA using small cell lung cancer (SCLC) cell was investigated. PACAP-27 (100 nM) increased c-fos mRNA 5-fold using NCI-N417 cells. The increase was concentration dependent with 0.1 nM PACAP-27 half maximally increasing c-fos mRNA. Also the increase in c-fos mRNA caused by PACAP was time dependent; being maximal after 1 hour and returning to basal values after 4 hours. PACAP-38 but not PACAP(28-38) increased c-fos mRNA. One uM PACAP(6-38), a PACAP receptor antagonist, inhibited the increase in c-fos mRNA caused by 1 nM PACAP. These data indicate that PACAP stimulates nuclear oncogene expression in SCLC cells.

Topics: Carcinoma, Small Cell; Dose-Response Relationship, Drug; Genes, fos; Humans; Kinetics; Lung Neoplasms; Neuropeptides; Neurotransmitter Agents; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Proto-Oncogene Proteins c-fos; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Count; Cell Division; Cell Line; DNA, Neoplasm; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Thymidine; Transplantation, Heterologous; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

To determine whether inappropriately secreted vasodilatory peptides have a role in the pathogenesis of orthostatic (postural) hypotension, a recognised paraneoplastic effect of bronchial malignancies usually attributed to immune mediated destruction of autonomic ganglia.. Serum concentrations of three vasodilatory peptides, atrial natriuretic peptide (ANP), vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP), were measured in 111 patients with bronchial carcinoma and 35 controls prospectively screened for orthostatic hypotension (> 20 mmHg drop in systolic blood pressure on repeated occasions on standing from the supine position) and in whom other causes of this condition were excluded.. Twenty two (20%) patients with carcinoma and two (6%) controls had orthostatic hypotension according to the criteria used. Serum concentrations of ANP, VIP and CGRP were elevated above normal in, respectively, 25 (23%), 10 (9%) and eight (7%) patients with carcinoma and in six (18%), zero and three (9%) controls. There was no correlation between orthostatic hypotension and concentrations of any of the vasodilatory peptides.. Elevated serum concentrations of ANP and CGRP were no more frequent in subjects with bronchial carcinoma than in controls and could not be attributed to the tumour, although there was a possible association for VIP. Orthostatic hypotension was more common in patients with carcinoma, but there was no evidence that the peptides measured played a role in its pathogenesis.

Topics: Aged; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Case-Control Studies; Humans; Hypotension, Orthostatic; Lung Neoplasms; Middle Aged; Paraneoplastic Syndromes; Prospective Studies; Vasoactive Intestinal Peptide

The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression.

Topics: Base Sequence; Bombesin; Bronchi; Carcinoma, Non-Small-Cell Lung; Cell Division; Humans; Lung Neoplasms; Molecular Sequence Data; Neprilysin; Receptors, Bombesin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

This study examines the roles of peptides and nitric oxide (NO) as mediators of inhibitory nonadrenergic, noncholinergic (NANCi) neurons in human and guinea pig airways in vitro. Tissues were contracted with 0.3 microM methacholine (MCh) and relaxation studied before and after the addition of the peptidase alpha-chymotrypsin (alpha-CT) (2 U/ml) and NG-nitro-L-arginine methyl ester (L-NAME 0.1-1.1 mM), an inhibitor of NO synthase, the enzyme catalyzing the formation of NO. alpha-CT alone, in comparison to parallel time controls, inhibited control relaxation to electrical field stimulation (EFS) by 29.2 +/- 8.6% in guinea pig tracheae (n = 9), whereas a small augmentation of relaxation was observed in human bronchi (n = 7). L-NAME inhibited the NANCi response in both guinea pig tracheae and human bronchi: in guinea pig tracheae, maximal inhibition of the alpha-CT-insensitive relaxation was 59.3 +/- 11.5% (SE, P = 0.003) at low frequencies (4-16 Hz) and 28.6 +/- 8.9% (P = 0.08) at 32 Hz; in human bronchi, the maximal inhibition was 37.7 +/- 9.3% (P = 0.008) at 8 or 16 Hz, and 37.9 +/- 5.9% (P = 0.005) at 32 Hz. Inhibition was greater after repeated baseline EFS for 90 min before initiation of contraction with MCh and addition of L-NAME (59.8 +/- 13.9% after repeated baseline EFS, n = 4; vs. 34.9 +/- 6.2% without repeated baseline EFS, n = 9, P = 0.025). Relaxant responses to sodium nitroprusside, vasoactive intestinal peptide, and isoproterenol were not affected by L-NAME. L-Arginine (10 mM), a precursor of NO, partially reversed the effect of L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Bronchi; Chymotrypsin; Dose-Response Relationship, Drug; Electric Stimulation; Female; Guinea Pigs; Humans; In Vitro Techniques; Isoproterenol; Lung Neoplasms; Male; Methacholine Chloride; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Trachea; Vasoactive Intestinal Peptide

Small-cell lung cancer (SCLC) is a common and highly fatal malignancy for which there is no satisfactory treatment. The amphibian peptide bombesin and its mammalian counterpart, gastrin-releasing peptide, serve as autocrine growth factors for the SCLC cells, but little is known about endogenous substances that inhibit the growth and proliferation of these tumor cells. We report that the neuropeptide vasoactive intestinal peptide (VIP) markedly inhibits the growth and multiplication of SCLC cell lines NCI-H345 and NCI-H69, and that the closely related peptide helodermin inhibits the proliferation of NCI-H345 cells with even higher efficacy. In the latter cells, the inhibition by VIP and isobutyl methyl xanthine paralleled their ability to stimulate cyclic adenosine monophosphate production within the cells. The peptide-induced suppression of SCLC proliferation is enhanced in the presence of an anti-bombesin monoclonal antibody. The antimitogenic activities of VIP and helodermin, and their enhancement by anti-bombesin antibody, offer the potential for a new approach to the pharmacologic control of SCLC.

Topics: Antibodies, Monoclonal; Bombesin; Carcinoma, Small Cell; Cell Division; Cell Line; Dose-Response Relationship, Drug; Humans; Intercellular Signaling Peptides and Proteins; Kinetics; Lung Neoplasms; Peptides; Time Factors; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Venoms

The most prevalent lung cancer, non-small cell lung cancer (NSCLC) has receptors for vasoactive intestinal peptide (VIP). Here the effects of a VIP antagonist (VIP-hyb) on NSCLC growth were investigated. In vivo, when VIPhyb (10 micrograms, s.c.) was daily injected into nude mice, xenograft formation was significantly inhibited by approximately 80%. In vitro, VIP (100 nM) stimulated colony formation approximately 2-fold, whereas 1 microM VIPhyb inhibited colony formation by approximately 50% when adenocarcinoma cell line NCI-H838 was used. The attenuation of tumor proliferation is receptor mediated, as VIPhyb inhibited specific 125I-labeled VIP binding to cell lines NCI-H157 and NCI-H838 with an IC50 of 0.7 microM. VIP (10 nM) increased the cAMP levels 5-fold when cell line NCI-H838 was used, and 10 microM VIPhyb inhibited the increase in cAMP caused by VIP. Northern blot analysis and radioimmunoassays have shown VIP mRNA and VIP-like immunoreactivity in NSCLC cells. These data suggest that VIP may be a regulatory peptide in NSCLC and that VIPhyb is a VIP receptor antagonist that inhibits proliferation.

Topics: Amino Acid Sequence; Animals; Carcinoma, Non-Small-Cell Lung; Cell Division; Gene Expression; Growth Inhibitors; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Neoplasms, Experimental; Neurotensin; Peptides; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Recombinant Fusion Proteins; RNA, Messenger; Transplantation, Heterologous; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

We describe the microscopic, histochemical, immunohistochemical, and ultrastructural features of hundreds of neuroendocrine tumorlets occurring within a pulmonary lobe severely scarred by intralobar sequestration in a nonsmoking 49-year-old white man. To our knowledge, there have thus far been no descriptions or detailed analyses of neuroendocrine tumorlets arising within a pulmonary sequestration. The neuroendocrine tumorlets appeared in the form of minute aggregates--mostly microscopic, up to a maximum of 0.3 cm in greatest diameter--of small round and short spindle-shaped cells. They were organized in compact nests of fascicles and were supplied with round or elongated euchromatic nuclei and scant weakly eosinophilic cytoplasm. The neuroendocrine tumorlets were clustered around diseased bronchioles or embedded in a fibrotic pulmonary parenchyma with a distinctive infiltrative appearance. Sometimes they lay near an artery channel without an identifiable bronchiole or herniated into distal airways. Most of the neuroendocrine tumorlets were strongly argyrophilic on Grimelius staining. Immunohistochemically, there was reactivity for markers of epithelial and neuroendocrine differentiation together with evidence of orthotopic production of calcitonin, serotonin, and gastrin-releasing peptide and ectopic production of vasoactive intestinal peptide. Ultrastructurally, most of the neuroendocrine cells showed 100- to 120-nm dense-core membrane-bound secretory granules; mucus secretory cells were also present. We prefer the term neuroendocrine tumorlets over the generally used term carcinoid tumorlets, because the nature of these lesions is undefined and the relationship with neuroendocrine pulmonary neoplasms is not yet established.

Topics: Calcitonin; Cell Nucleus; Chromogranins; Cytoplasm; Cytoplasmic Granules; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Male; Microscopy, Electron; Middle Aged; Neurosecretory Systems; Peptides; Phosphopyruvate Hydratase; S100 Proteins; Serotonin; Staining and Labeling; Vasoactive Intestinal Peptide

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) stimulated the growth of murine Lewis lung carcinoma cells in culture. The growth promoting effect was dependent on the concentration of VIP. Exposure to VIP for 12 hours followed by removal of the peptide resulted in sustained growth promotion for 4 to 5 days in culture. Synthetic fragments of VIP, i.e., VIP (1-16) and VIP (22-28), and the unrelated peptide neurotensin failed to stimulate the growth of the Lewis lung carcinoma cells. The growth-promoting effect of VIP was also observed in a murine mammary tumor cell line and a human lung adenocarcinoma cell line.

Topics: Adenocarcinoma; Animals; Cell Division; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neurotensin; Peptide Fragments; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Biomarkers, Tumor; Bombesin; Gastrins; Glucagon; Hormones; Humans; Immunophenotyping; Lung Neoplasms; Male; Middle Aged; Somatostatin; Vasoactive Intestinal Peptide

High levels of BN/GRP are present in classic SCLC and lung carcinoids, whereas BN immunoreactivity is absent in variant SCLC, adenocarcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma cell lines. BN-like peptides are secreted from classic SCLC into the tissue culture medium. The secretion rate of BN-like peptides from cell line NCI-H345 was increased 3-fold by VIP (1 microM). Also, VIP increased the cAMP levels in cell line NCI-H345 by an order of magnitude. Therefore, SCLC cells have functional VIP receptors which regulate the secretion of BN-like peptides. Also, SRIF (100 nM) inhibits the VIP-stimulated increase in cAMP levels and secretion rate of BN-like peptides from SCLC cells. Because BN stimulates colony formation, VIP and/or SRIF may be able to alter the growth of SCLC cells. BN-like peptides are secreted from SCLC cells into the plasma. The levels of BN immunoreactivity in the plasma of SCLC patients with extensive disease is 2- to 40-fold greater than that of patients with limited disease. Secretin infusion into patients with extensive disease produces a transient increase (7-fold) in the plasma concentration of BN-like peptides. BN-like peptides are also present in the CSF of SCLC patients. When released from SCLC cells, BN-like peptides may interact with cell surface receptors. [Tyr4]BN binds with high affinity (Kd = 0.5 nM) to a single class of sites (1500/cell) on cell line NCI-H345. The carboxyl terminus of BN or GRP is essential for high-affinity binding activity. BN-like peptides elevate cytosolic Ca2+ levels as a result of increased phosphatidylinositol turnover. The putative BN receptor antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P inhibits high-affinity [Tyr4]BN binding, the ability of BN to elevate cytosolic Ca2+ levels, and colony formation of SCLC cells. Therefore, BN receptor antagonists may serve as useful agents to inhibit the growth of SCLC.

Topics: Bombesin; Carcinoma, Small Cell; Cell Line; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Peptides; Receptors, Bombesin; Receptors, Neurotransmitter; Secretin; Vasoactive Intestinal Peptide

The effects of somatostatin (SRIF) on small cell lung cancer (SCLC) cell line NCI-H345 was investigated. SRIF had no effects on the basal cAMP levels or the secretion rate of bombesin-like peptides. VIP (1 microM) increased the cAMP levels approximately 10-fold and the secretion rate of bombesin-like peptides 3-fold. SRIF and its analogues inhibited the increase in the cAMP levels and the secretion rate of bombesin-like peptides caused by VIP. The order of peptide potency was (D-Trp8)SRIF > SRIF-28 = (Tyr11)SRIF > SRIF. These data suggest that functional SRIF receptors may be present on SCLC cells.

Topics: Bombesin; Carcinoma, Small Cell; Cyclic AMP; Lung Neoplasms; Peptides; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Somatostatin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Plasma samples from 21 patients with small cell carcinoma of the lung were screened for pancreatic polypeptide, somatostatin, motilin, and vasoactive intestinal polypeptide. One patient had severe impairment of both renal and liver function. In the 20 remaining subjects vasoactive intestinal polypeptide concentrations were normal, and only two patients had increased concentrations of somatostatin. Increases in pancreatic polypeptide were detected more commonly (7/20), but these may have been non-specific age related increases. The major finding was high concentrations of motilin (greater than 496 pg/ml) in 17 of 20 patients. Plasma motilin was subsequently assayed in 16 more patients with lung cancer, including 10 patients with non-small cell carcinoma of the lung. At concentrations over 900 pg/ml plasma motilin appears to be a tumour marker for small cell carcinoma of the lung with acceptable sensitivity (59%) and specificity (78%). The origin of increased plasma motilin in small cell carcinoma of the lung was investigated. Bombesin (gastrin releasing peptide), a peptide known to stimulate the release of motilin in man, was, as in previous studies, detected in tumour but not in plasma, except in one patient out of 21. Immunohistochemical studies failed to detect motilin antigen in biopsy samples. Motilin tumour content was found to be low in tumour tissue from three patients with small cell carcinoma of the lung who had appreciable hypermotilinaemia and from three patients with non-small cell carcinoma of the lung who had either normal or slightly raised plasma motilin concentrations. The stimulus to motilin secretion in patients with small cell carcinoma of the lung remains unclear.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Motilin; Pancreatic Polypeptide; Prospective Studies; Retrospective Studies; Somatostatin; Vasoactive Intestinal Peptide

Paraffin-embedded specimens from a total of 94 small-cell carcinomas of the lung (SCCL) were screened for immunoreactivity to nine different peptide hormones (ACTH, calcitonin, gastrin, glucagon, growth hormone, human chorion gonadotropin, insulin, somatostatin and vasoactive intestinal peptide, VIP) using an indirect immunoperoxidase technique with commercially available kits. Special attention was focused on the prognostic significance of the peptide immunoreactivity. A total of 32 carcinomas (34%) showed immunoreactivity to one or more peptide hormones, the cases with ACTH reactivity (24.5%) far outnumbering those with reactivity to calcitonin (1.1%), somatostatin (1.1%), VIP (3.3%) or multiple peptides (4.3%). The mean survival of the patients was 8.4 months, being shorter (7.3 months) for the SCCLs with peptide reactivity than for the nonreactive carcinomas (9.2 months). The most favorable survival was found in VIP-reactive tumors (20.5 months), and the worst (2.0 months) in cases reactive to multiple peptides. The results suggest that immunohistochemical screening of the SCCL biopsies for the peptide hormones might be of benefit in predicting the clinical outcome of the disease.

Topics: Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Small Cell; Histocytochemistry; Hormones; Humans; Immunoenzyme Techniques; Lung Neoplasms; Prognosis; Somatostatin; Vasoactive Intestinal Peptide

Bombesin/gastrin releasing peptide-like immunoreactivity (BLI) is found in the majority of small cell carcinoma of the lung (SCCL) cell lines examined. Because BLI is present in high concentration in SCCL we studied the mechanism of BLI secretion from several SCCL cell lines and in patients with SCCL. In cell line NCI-H345 the structurally related polypeptide hormones secretin, vasoactive intestinal peptide, and peptide histidine isoleucine as well as theophylline, a phosphodiesterase inhibitor, N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate, a cyclic nucleotide analogue, increased BLI release by 16-120% and cyclic adenosine 3':5'-monophosphate by 36-350%. Similar results were obtained in SCCL cell line NCI-H209. i.v. injection of secretin (2 units/kg) significantly increased plasma BLI in 2 patients with extrapulmonary SCCL. These data suggest that SCCL cells possess receptors for secretin/vasoactive intestinal peptide and that receptor occupation stimulates in vitro and in vivo BLI secretion.

Topics: Alprostadil; Bombesin; Bucladesine; Carcinoma, Small Cell; Cyclic AMP; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Peptide PHI; Peptides; Secretin; Secretory Rate; Theophylline; Time Factors; Vasoactive Intestinal Peptide

There is increasing evidence in many species that vasoactive intestinal peptide (VIP) may be a neurotransmitter in nonadrenergic inhibitory nerves. We have studied the effect of electrical field stimulation (EFS), exogenous VIP, and isoproterenol (Iso) on human airways in vitro. We have also studied a related peptide, peptide histidine methionine (PHM), which coexists with VIP in human airway nerves, and in separate experiments studied fragments of the VIP amino acid sequence (VIP1-10 and VIP16-28) for agonist and antagonist activity. Human airways were obtained at thoracotomy and studied in an organ bath. In bronchi EFS gave an inhibitory response that was unaltered by 10(-6) M propranolol but was blocked by tetrodotoxin, whereas in bronchioles there was little or no nonadrenergic inhibitory response. VIP, PHM, and Iso all caused dose-dependent relaxation of bronchi, VIP and PHM being approximately 50-fold more potent than Iso. VIP, but not Iso, mimicked the time course of nonadrenergic inhibitory nerve stimulation. In contrast bronchioles relaxed to Iso but not to VIP or PHM. Neither propranolol nor indomethacin altered the relaxant effects of VIP or PHM, suggesting a direct effect of these peptides on airway smooth muscle. Neither of the VIP fragments showed either agonist or antagonist activity. We conclude that VIP and PHM are more potent bronchodilators of human bronchi than Iso and that the association between the relaxant effects of these peptides and nonadrenergic inhibitory responses suggests that they may be possible neurotransmitters of nonadrenergic inhibitory nerves in human airways.

Topics: Bronchi; Humans; In Vitro Techniques; Indomethacin; Lung; Lung Neoplasms; Muscle, Smooth; Peptide PHI; Propranolol; Vasoactive Intestinal Peptide

We have attempted to characterize a group of bronchopulmonary neoplasms that share certain structural features with true carcinoids but appear distinctly more pleomorphic and behave far more aggressively. In reviewing our files from 1973 to 1982, 11 such neoplasms were identified; the original diagnoses were "atypical bronchial carcinoid" (3 cases), "malignant carcinoid" (1 case), "bronchial carcinoid" (3 cases), "peripheral carcinoid" (2 cases), and "peripheral oat cell carcinoma" (2 cases). Of the 11 neoplasms, 5 were central and 6 were peripherally located. At presentation, 7 patients had lymph node metastases and 1 had a distant metastasis. No patient had a conventionally defined hormonal syndrome; however, 2 patients had a history of episodic flushing, one of which was associated with diarrhea. All cases were studied by light microscopy and light microscopic immunohistochemistry for NSE (neuron-specific enolase), serotonin, and broad-spectrum neuropeptides. Five cases were studied by electron microscopy. By light microscopy, the tumors were composed of solid clusters of polygonal to fusiform cells in an evident organoid arrangement. Foci of glandular and/or squamous differentiation were seen in 7 cases. Pleomorphism was moderate and mitoses were readily found. Focal necrosis was seen. By immunohistochemistry, 10 cases expressed NSE immunoreactivity. All cases demonstrated hormonal immunoreactivity; in 9 cases, immunoreactivity for more than one hormone was observed. The hormones most frequently expressed were serotonin, bombesin, gastrin, leu-enkephalin, and ACTH. By electron microscopy, all cases studied contained heterogeneous populations of neurosecretory granules; the latter, however, were not abundant and tended to aggregate either in the basal pole of the cells or, more frequently, interlacing "dendritelike" cytoplasmic processes. Aggregates of intermediate filaments were frequently seen. Basal lamina deposition was seen but gaps and larger areas of discontinuity were frequent. We believe that these neoplasms constitute a distinct pathologic entity for which the term "well-differentiated neuroendocrine carcinoma" has been proposed. Clinically, these tumors merit special attention since they are demonstrably more aggressive than true carcinoids but are distinctly less malignant than the intermediate or small cell variants of neuroendocrine carcinoma.

Topics: Adult; Aged; Bombesin; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Adenoid Cystic; Chorionic Gonadotropin; Cytoplasmic Granules; Enkephalin, Leucine; Female; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Microscopy, Electron; Middle Aged; Serotonin; Somatostatin; Staining and Labeling; Vasoactive Intestinal Peptide

The cell source of peptide hormone production and the morphological differentiation were investigated in 18 adenocarcinomas of the lung by immunohistochemistry and/or by electron microscopy. These tumors were found by radioimmunoassay of tumor extracts to contain either one or more of 7 peptide hormones, i.e. adrenocorticotropin (ACTH), beta- and gamma-melanocyte stimulating hormones (MSH), somatostatin (SS), vasoactive intestinal polypeptide (VIP), gastrin releasing peptide (GRP) and calcitonin (CT). In a combined adeno- and small cell carcinoma, a considerable number of small tumor cells were positively stained for ACTH, beta- and gamma-MSHs and GRP. In a poorly differentiated adenocarcinoma with mucin and CT production, these products were localized in some single cells. Electron microscopy revealed secretory granules indistinguishable from exocrine or endocrine types. In another mucin-positive adenocarcinoma with high SS and CT contents, some tumor cells were stained for SS and/or CT. Two distinct exocrine and endocrine type secretory granules were found in the same cells. In tumors with 100 ng or less of the peptides/g tissue, most tumor cells were not stained for the peptides but a small number showed morphological endocrine differentiation. In conclusion, a considerable proportion of the adenocarcinomas of the lung may show heterogeneous differentiation in both endocrine and exocrine directions.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Calcitonin; Cytoplasmic Granules; Gastrin-Releasing Peptide; Histocytochemistry; Hormones; Humans; Lung Neoplasms; Melanocyte-Stimulating Hormones; Microscopy, Electron; Peptide Biosynthesis; Somatostatin; Vasoactive Intestinal Peptide

Topics: 1-Methyl-3-isobutylxanthine; Carcinoma, Squamous Cell; Cell Line; Cyclic AMP; Gastrointestinal Hormones; Humans; Isoproterenol; Lung Neoplasms; Neoplasms, Experimental; Prostaglandins E; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Secretin; Temperature; Time Factors; Vasoactive Intestinal Peptide

Among the metabolic functions of the lungs are the formation, release, activation and inactivation of biologically active peptides. The following peptides may be present or formed in normal lung: vasoactive intestinal peptide or a peptide closely related to it, a spasmogenic peptide not yet fully identified, bradykinin, substance P, a bombesin-like peptide (especially in fetal and neonatal lung), and eosinophil-chemotactic peptides. These peptides are found in special neuroendocrine cells, in neurons, or in mast cells. Normal lung also inactivates bradykinin and activates angiotensin; both processes are catalysed by the same enzyme (kininase II or angiotensin-converting enzyme), located in pulmonary vascular endothelium. Pulmonary tumours and certain non-tumorous lesions can produce and release a variety of peptide hormones that are not normally generated by the lung in substantial amounts. This 'ectopic' secretion of hormones may be detectable only by sensitive assays or may result in specific clinical syndromes.

Topics: Animals; Bombesin; Bradykinin; Gastrointestinal Hormones; Humans; Lung; Lung Neoplasms; Muscle, Smooth; Peptides; Peptidyl-Dipeptidase A; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma; Adrenal Cortex Hormones; Carcinoma, Bronchogenic; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

By means of a statistical analysis of the occurrence of amino-acid residues in the polypeptide chains of several gastro-entero-pancreatic (GEP) hormones an investigation was undertaken to determine whether any of these hormones might be related to each other--possibly from an evolutionary point of view. Particular interest was paid to the occurrence of small charged segments, i.e. those with acidic or basic amino acid residues, since such segments can be presumed to play a role in hormonal receptor binding mechanisms. By this method hormonal relationships were suggested by the observation that these small charged amino-acid sequences, contained in the hormonal structures, match as a result of non-randomness. It was found that hagfish and human insulin were related on a molecular level not only to the newly discovered (avian, bovine, human) pancreatic polypeptide (PP) but also to some other GEP hormones (VIP, GIP, glucagon) as well as to calcitonin and to the alpha-subunit of the glycoprotein hormones. Interpretation of the statistical data suggests that all these peptide hormones are related by a common hexapeptide sequence which contributed, at an evolutionary point, to their molecular architecture. A hexapeptide segment of APP is statistically related to a sequence of equal size in the carboxy terminal region of the A-chain of both hagfish and human insulin, providing the first instance of their structural similarity. Correlations between PP, insulin, glucagon, VIP, and calcitonin provide a tentative basis for predicting the production of one or more of these peptide hormones by immature or de-differentiated cells of neoplasms and non-neoplastic pathologic lesions of the GEP endocrine system.

Topics: Amino Acid Sequence; Animals; Biological Evolution; Calcitonin; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glycoproteins; Humans; Insulin; Lung Neoplasms; Mathematics; Molecular Conformation; Pancreatic Hormones; Peptides; Statistics as Topic; Vasoactive Intestinal Peptide

Levels of vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay in plasma or tissue from thirty-five patients with watery diarrhoea, and in plasma of twenty-five normal controls. Plasma levels were between 0.6 and 11.0 ng/ml in thirty-one of the thirty-three patients in whom it was measured and too low to measure (less than 200 pg/ml) in the other two. Peptide levels were less than 200 pg/ml in twenty-three of the controls, but higher in the remaining two. All tissues from patients were "rich" in VIP (10 ng to 35 microgram per g). The aetiologic diagnoses included pancreatic islet-cell adenoma or adenocarcinoma, islet-cell hyperplasia, bronchogenic carcinoma, pheochromocytoma, ganglioneuroblastoma, medullary thyroid carcinoma, and retroperitoneal histiocytoma. The findings support the conclusions that: (1) VIP is a likely mediator of the water-diarrhoea syndrome; (2) the syndrome may result from a variety of tumours; (3) this or a related peptide hormone may be secreted by these tumours; and (4) these tumours may have a common embryonic origin.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; APUD Cells; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Radioimmunoassay; Thyroid Neoplasms; Vasoactive Intestinal Peptide