vasoactive-intestinal-peptide and Neoplasms

To review and discuss the available international literature regarding the indirect and direct biochemical mechanisms that occur after exercise, which could positively, or negatively, influence oncogenic pathways.. The PubMed, MEDLINE, Embase and Cochrane libraries were searched for papers up to July 2016 addressing biochemical changes after exercise with a particular reference to cancer. The three authors independently assessed their appropriateness for inclusion in this review based on their scientific quality and relevance.. 168 papers were selected and categorised into indirect and direct biochemical pathways. The indirect effects included changes in vitamin D, weight reduction, sunlight exposure and improved mood. The direct effects included insulin-like growth factor, epigenetic effects on gene expression and DNA repair, vasoactive intestinal peptide, oxidative stress and antioxidant pathways, heat shock proteins, testosterone, irisin, immunity, chronic inflammation and prostaglandins, energy metabolism and insulin resistance.. Exercise is one of several lifestyle factors known to lower the risk of developing cancer and is associated with lower relapse rates and better survival. This review highlights the numerous biochemical processes, which explain these potential anticancer benefits.

Topics: Carcinogenesis; Energy Metabolism; Epigenesis, Genetic; Exercise; Fibronectins; Heat-Shock Proteins; Humans; Inflammation; Insulin Resistance; Life Style; Neoplasms; Oxidative Stress; Prostaglandins; Somatomedins; Testosterone; Vasoactive Intestinal Peptide

To summarize the roles of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptide (PACAP) and their receptors (VPAC1, VPAC2, PAC1) in human tumors as well as their role in potential novel treatments.. Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially in the role of transactivation of the epidermal growth factor family. The overexpression of VPAC1/2 and PAC1 on a number of common neoplasms (breast, lung, prostate, central nervous system and neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues.. VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery are all suggesting possible novel tumor treatments.

Topics: Humans; Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide

Neuropeptides are potentially valuable tools for clinical applications as they offer many distinct advantages over other bioactive molecules like proteins and monoclonal antibodies due to their reduced side effects and simple chemical modifications. Despite such advantages, the difficulty with neuropeptides often relies on their poor metabolic stability and reduced biological activity intervals. Among the neuropeptides, VIP has been identified as a potentially bioactive agent for inflammatory, neurodegenerative, and cancer-related diseases. However, the effective translation of preclinical studies related to VIP to clinical realities faces several major challenges, most of which are commonplace for other neuropeptides. Here, we present recent studies aimed at developing nanostructured organic and inorganic systems either for the appropriate delivery of VIP or for VIP targeting. These technologies stand as an alternative starting point for chemical manipulations of the neuropeptides in order to improve potency, selectivity, or pharmacokinetic parameters.

Topics: Antineoplastic Agents; Drug Delivery Systems; Gene Expression; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Protein Binding; Receptors, Vasoactive Intestinal Peptide; Static Electricity; Translational Research, Biomedical; Vasoactive Intestinal Peptide

Nuclear medicine techniques are becoming more important in imaging oncological and infectious diseases. For metabolic imaging of these diseases, antibody and peptide imaging are currently used. In recent years peptide imaging has become important, therefore the rationale for the use of peptide imaging is described in this article. Criteria for a successful peptide tracer are a high target specificity, a high binding affinity, a long metabolic stability and a high target-to-background ratio. Tracer internalization is also beneficial. For oncological imaging, many tracers are available, most originating from regulatory peptides, but penetrating peptides are also being developed. Peptides for imaging inflammatory and infectious diseases include regulatory peptides, antimicrobial peptides and others. In conclusion, for the imaging of oncological, imflammatory and infectious diseases, many promising peptides are being developed. The ideal peptide probe is characterized by rapid and specific target localization and binding with a high tumour-to-background ratio.

Topics: Antimicrobial Cationic Peptides; Bombesin; Cholecystokinin; Gastrin-Releasing Peptide; Glucagon-Like Peptide 1; Humans; Infections; Inflammation; Isotope Labeling; Neoplasms; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Somatostatin; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) conveys various physiological effects in the digestive tract, nervous and cardiovascular system, airways, reproductive system, endocrine system, and more. A family of specific membrane bound receptors, termed VPAC1, VPAC2, and PAC1, bind VIP and trigger the effects. Many of them are of clinical interest. To date more than two thousand publications suggest the use of VIP in diseases like asthma, erectile dysfunction, blood pressure regulation, inflammation, endocrinology, tumours, etc. Despite this considerable potential, the peptide is not regularly used in clinical settings. A key problem is the short half life of inhaled or systemically administered VIP due to rapid enzymatic degradation. This shortcomings could be overcome with stable derivates or improved pharmacokinetics. A promising strategy is to use biocompatible and degradable depots, to protect the peptide from early degradation and allow for controlled release. This review focuses on aspects of clinical applications of VIP and the idea to use formulations based on biodegradable particles, to constitute a dispersible VIP-depot. Smart particle systems protect the peptide from early degradation, and assist the sustainable cell targeting with VIP for therapeutic or imaging purposes.

Topics: Administration, Inhalation; Animals; Asthma; Drug Carriers; Gastrointestinal Agents; Humans; Hypertension, Pulmonary; Liposomes; Nanoparticles; Neoplasms; Neuroprotective Agents; Protamines; Pulmonary Disease, Chronic Obstructive; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide; Vasodilator Agents

The effects of vasoactive intestinal peptide (VIP) on the proliferation of central nervous system (CNS) and cancer cells were investigated. VIP has important actions during CNS development. During neurogenesis, VIP stimulates the proliferation and differentiation of brain neurons. Addition of VIP to embryonic mouse spinal cord cultures increases neuronal survival and activity dependent neurotrophic factor (ADNF) secretion from astroglial cells. VIP is an integrative regulator of brain growth and development during neurogenesis and embryogenesis. Also, VIP causes increased proliferation of human breast and lung cancer cells in vitro. VIP binds with high affinity to cancer cells, elevates the cAMP and increases gene expression of c-fos, c-jun, c-myc and vascular endothelial cell growth factor. The effects of VIP on cancer cells are reversed by VIPhybrid, a synthetic VPAC(1) receptor antagonist. VIPhyb inhibits the basal growth of lung cancer cells in vitro and tumors in vivo and potentiates the ability of chemotherapeutic drugs to kill cancer cells. Due to the high density of VPAC(1) receptors in cancer cells, VIP has been radiolabeled with 123I, 18F and 99mTc to image tumors. It remains to be determined if radiolabeled VIP analogs will be useful agents for early detection of cancer in patients.

Topics: Amino Acid Sequence; Animals; Central Nervous System; Humans; Molecular Sequence Data; Neoplasms; Second Messenger Systems; Sequence Homology, Amino Acid; Vasoactive Intestinal Peptide

Bone cells respond in specific ways to various hormones and growth factors, but the biology of skeletal innervation and its physiologic significance in bone metabolism is poorly understood. With the introduction of immunohistochemical staining techniques and new molecular biology tools, the knowledge in this field has significantly improved. In this review, we update current understanding of the effects of neuropeptides on bone metabolism, specifically vasoactive intestinal peptide (VIP) and calcitonin-gene related peptide (CGRP). In addition, new information concerning the role of growth factors, such as neurotrophins, is also discussed. There is strong evidence to suggest that bone can be a target of the nervous system. Further investigations in this field will allow us to answer questions related to pre-natal development, bone growth, fracture healing, osteoporosis, osteoarthritis or neoplasias of mesoderm origin.

Topics: Bone and Bones; Bone Development; Calcitonin Gene-Related Peptide; Embryonic and Fetal Development; Fracture Healing; Humans; Immunohistochemistry; Molecular Biology; Neoplasms; Nerve Growth Factors; Neuropeptides; Osteoarthritis; Osteoporosis; Vasoactive Intestinal Peptide

Imaging and therapy using radiolabeled monoclonal antibodies have proved useful in many clinical studies. However, immunogenicity of mouse antibodies to human and insufficient tumor-to-normal tissue ratios remained to be solved. Chimerization and humanization by genetic engineering, and multistep targeting techniques have enabled lower immunogenicity and higher tumor-to-normal tissue contrast. Peptides like somatostatin-analogs have been reportedly useful in imaging tumors, which are either somatostatin receptor positive or negative. Elevated normal tissue accumulation of radiolabeled peptides is a drawback in aiming internal radiation therapy.

Topics: Animals; Antibodies, Monoclonal; Humans; Indium Radioisotopes; Iodine Radioisotopes; Mice; Neoplasms; Octreotide; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Vasoactive Intestinal Peptide

Topics: Adult; Amino Acid Sequence; Animals; Antineoplastic Agents; Cell Division; Child; Humans; Mammals; Mitosis; Molecular Sequence Data; Neoplasms; Receptors, Vasoactive Intestinal Peptide; Sequence Homology, Amino Acid; Vasoactive Intestinal Peptide

Topics: Animals; Gastrin-Releasing Peptide; Gastrins; Growth Substances; Humans; Kinins; Neoplasms; Neuropeptides; Neurotensin; Peptides; Vasoactive Intestinal Peptide; Vasopressins

Topics: Adrenocorticotropic Hormone; APUD Cells; Bombesin; Cell Differentiation; Chorionic Gonadotropin; Corticotropin-Releasing Hormone; Endorphins; Gene Expression Regulation; Gonadotropins; Growth Hormone; Growth Hormone-Releasing Hormone; Hormones, Ectopic; Humans; Insulin; Lymphokines; Mutation; Neoplasms; Parathyroid Hormone; Prolactin; Prostaglandins; Somatostatin; Thyrotropin; Vasoactive Intestinal Peptide; Vasopressins

Gut peptide secreting tumours originate most commonly from the pancreatic Islets of Langerhans. Tumours at a variety of other sites have also been shown to synthesize and release these peptides, reflecting the wide distribution of the peptide secreting cells of the diffuse neuroendocrine system. Tumours such as the glucagonomas, insulinomas, VIPomas and gastrinomas are associated with characteristic clinical syndromes resulting from the effects of the peptide they secrete. The majority of the islet cell tumours in fact secrete a number of different peptides and many of these are present in several molecular forms, some of which may not be biologically active. This may explain the lack of clinical sequelae in association with tumours such as the somatostatinomas. The clinical features, methods of diagnosis, localisation and treatment of these tumours will be discussed.

Topics: Adenoma, Islet Cell; Bombesin; Bronchial Neoplasms; C-Peptide; Carcinoma, Small Cell; Diagnosis, Differential; Endocrine System Diseases; Erythema; Gastrointestinal Hormones; Glucagon; Glucagonoma; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Neoplasms; Neurotensin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatinoma; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Information concerning GEP hormones has progressively advanced since the initial discovery of a GEP hormone, secretin, in 1902. Studies in this area flourished with the advent of radioimmunoassay, and have provided an understanding of the secretion, regulation, metabolic actions, and role in certain diseases of major GEP hormones. Measurement of GEP hormones has achieved importance in clinical medicine and allowed understanding of the pathophysiology of several clinical disorders. The decade to come should witness additional advances in this rapidly expanding field.

Topics: Chemical Phenomena; Chemistry; Cholecystokinin; Diabetes Mellitus; Diarrhea; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypoglycemia; Motilin; Neoplasms; Neurotensin; Pancreatic Polypeptide; Peptic Ulcer; Secretin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Cholecystokinin; Gastric Juice; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Precancerous Conditions; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

A female patient aged 77 years had refractory watery diarrhea caused by a vasoactive intestinal peptide production tumor. She had impaired consciousness. After presenting to our hospital, we administered opium tincture, after which the diarrhea ceased. Intravenous feeding was able to be stopped along with the potassium load and the infusion of octreotide, and loperamide. The antidiarrheal effects continued after opium tincture was stopped, and the patient was discharged home. These results reveal that opium tincture can be efficacious in treating end-stage refractory diarrhea.

Topics: Aged; Diarrhea; Female; Humans; Neoplasms; Octreotide; Opium; 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

The receptors for vasoactive intestinal peptide (VIP), VPAC1-, VPAC2-, and PAC1-receptor are overexpressed by various tumor cells. VIP can target these receptors and transport conjugates into the cell. However, the use of VIP for tumor cell targeting is hampered by the peptides short half-lives due to enzymatic degradation. Because protamine-based nanoparticles (proticles) protect the peptide and serve as peptide depot, we explored the potential of proticles as carrier for VIP-conjugated molecules. The VIP-loaded proticles were stable as shown by Fluorescence Correlation Spectroscopy. With Confocal Laser Scanning Microscopy, we observed VIP-loaded proticles to specifically target the tumor cells. The cell binding triggered the substance release and conjugate internalization of VIP-Cy3 in vitro and ex vivo by human tumors. We observed VIP releasing proticle depots distributed in rat tissue and human tumors. Our findings warrant further studies to explore the proticles potential to enable peptide-mediated targeting for in vivo and clinical applications.

Topics: Animals; Arteries; Cell Line, Tumor; Drug Stability; Humans; Immunohistochemistry; In Vitro Techniques; Nanoparticles; Neoplasms; Particle Size; Protamines; Rats; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Spectrometry, Fluorescence; Vasoactive Intestinal Peptide; Vasodilation

Vasoactive intestinal peptide (VIP) is an interesting example of a 28-amino acid neuropeptide that is abundantly expressed in discrete brain regions/neurons and hence may contribute to brain function. This short review summarizes my own point of view and encompasses 25 years of work and over 100 publications targeting the understanding of VIP production and biological activity. The review starts with our original cloning of the VIP gene, it then continues to discoveries of regulation of VIP synthesis and the establishment of the first VIP transgenic mice. The review ends with the identification of novel VIP analogs that helped decipher VIP's important role during development, in regulation of the biological clock(s) and diurnal rhythms, sexual activity, learning and memory as well as social behavior, and cancer. This review cites only articles that I have coauthored and gives my own perspective of this exciting ever-growing field.

Topics: Amino Acid Sequence; Animals; Biological Clocks; Brain; Cell Proliferation; Cyclic AMP; Cytokines; History, 20th Century; History, 21st Century; Humans; Intercellular Signaling Peptides and Proteins; Molecular Sequence Data; Neoplasms; Research; RNA, Messenger; Sequence Alignment; Synapses; Vasoactive Intestinal Peptide

In an effort to develop a peptide-based radiopharmaceutical for the detection of tumors overexpressed vasoactive intestinal peptide receptors with positron emission tomography, we have prepared a novel [R(8,15,21), L17]-VIP peptide for 18F-labeling. This peptide inhibited 125I-VIP binding to rats lung membranes with high affinity [half-maximal inhibitory concentrations (IC50) of 0.12 nm]. Additionally, [R(8,15,21), L17]-VIP showed higher stability than native vasoactive intestinal peptide in vivo of mice. With N-succinimidyl 4-[18F] fluorobenzoate as labeling prosthetic group, [18F]FB-[R(8,15,21), L17]-VIP was obtained in >99% radiochemical purity within 100 min in decay-for-corrected radiochemical yield of 33.6 +/- 3% (n = 5) and a specific radioactivity 255 GBq/micromol at the end of synthesis. Stability of [18F]FB-[R(8,15,21), L17]-VIP in vitro and in vivo were investigated. Biodistribution of this trace was carried out in mice with induced C26 colorectal tumor. Fast clearance of [18F]FB-[R(8,15,21), L17]-VIP from non-target tissues and specific uptakes by tumors realized higher tumor-to-muscle ratio (3.55) and tumor-to-blood ratio (2.37) 60 min postinjection. Clear difference was observed between the blocking and unblocking experiments in biodistribution and whole body radioautography. [18F]FB-[R(8,15,21), L17]-VIP has demonstrated its potential for diagnosing tumors overexpressed vasoactive intestinal peptide receptors both in vitro and in vivo.

Topics: Amino Acid Sequence; Animals; Cell Membrane; Colorectal Neoplasms; Iodine Radioisotopes; Lung; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Neoplasms; Peptides; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Inbred Strains; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Targeted delivery of radionuclides and therapeutic agents to specific biomarkers of breast cancer has important implications for the diagnosis and therapy of breast cancer. Vasoactive intestinal peptide receptors (VIP-R) are approximately five times more expressed in human breast cancer, compared to normal breast tissue. We have used VIP, a 28 amino acid mammalian neuropeptide, as a breast cancer targeting moiety for targeted imaging of breast cancer. VIP was covalently attached to the surface of sterically stabilized liposomes (SSL) that encapsulated a radionuclide, Tc99m-HMPAO. Rats with n-methyl nitrosourea (MNU)-induced in situ breast cancers were used to test this targeted liposomal imaging agent. Specifically, the pharmacokinetics and biodistribution of Tc99m-HMPAO encapsulating SSL with and without VIP were determined together with their ability to image breast cancer. The presence of VIP did not alter the size and Tc99m-HMPAO encapsulation ability of SSL. It also did not alter the pharmacokinetic profile of SSL. Long-circulating liposomes with and without VIP on their surface accumulated at significantly higher quantities in breast cancer when compared to normal breast, indicating passive targeting of these constructs to cancer tissues. Importantly, in breast cancer, Tc99m-HMPAO encapsulating SSL with VIP showed significantly more accumulation than SSL without VIP. The tumor to non-tumor ratio was also significantly higher for Tc99m-HMPAO encapsulating VIP-SSL than Tc99m-HMPAO encapsulating SSL without VIP, suggesting active targeting of VIP-SSL to breast cancer. Collectively, these data showed that Tc99m-HMPAO encapsulating VIP-SSL can be successfully used for the targeted imaging of breast cancer.

Topics: Animals; Carcinogens; Drug Carriers; Drug Compounding; Female; Image Processing, Computer-Assisted; Liposomes; Mammary Neoplasms, Experimental; Methylnitrosourea; Neoplasms; Particle Size; Radionuclide Imaging; Radiopharmaceuticals; Rats; Technetium Tc 99m Exametazime; Tissue Distribution; Vasoactive Intestinal Peptide

A possible cross-competition between vasoactive intestinal peptide (VIP) and somatostatin (somatotropin release inhibiting factor; SRIF) and their respective receptors, was investigated at native or recombinant SRIF and VIP/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. The activity of VIP was examined in radioligand binding assays at mouse sst(1-5), rat sst(1-2) and human sst(1-5) receptors; or at human tumours preferentially expressing each of the five SRIF receptors. Moreover, SRIF was investigated at human tumoral tissues known to exclusively express specific VIP/PACAP receptor(s). VIP had no significant effect on any of the radioligand binding sites of the SRIF receptor family of rat, mouse or human origin tested. Conversely, SRIF did not interfere with the human VIP/PACAP binding sites tested. Taken together, the results cast reservation on the claimed cross-competition between VIP and SRIF at, specifically human sst(3) receptors, or any of the cloned SRIF or VIP/PACAP receptors recognised to date.

Topics: Animals; Binding, Competitive; Cell Line; Dose-Response Relationship, Drug; Humans; Iodine Radioisotopes; Male; Mice; Neoplasms; Neuropeptides; Peptides, Cyclic; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Recombinant Proteins; Somatostatin; Vasoactive Intestinal Peptide

In recent years, imaging tumors with receptor-specific biomolecules has been the focus of increasing interest. Vasoactive intestinal peptide (VIP) has a high affinity for specific receptors that are expressed in high density on a large number of malignant tumors. VIP was modified (TP 3654) without compromising its biologic activity and labeled with 99mTc. Pharmacokinetics and feasibility studies were performed in 3 healthy volunteers and 11 patients with a history of cancer. Imaging was performed for up to 2 h after injection. Within 24 h after injection of 99mTc-TP 3654 (370-555 MBq/5 microg), approximately 70% of the tracer cleared through the kidneys and 20% through the liver. Blood clearance was rapid. No adverse reaction was noted in any subject. All known tumors were clearly delineated within 20 min. Findings were compared with the results of 99mTc-methoxyisobutyl isonitrile, CT, MRI, or histology. There was concordance in 9 patients. In the other 2 patients, only the VIP scan was positive for tumors known to express VIP receptors. The early results of imaging tumors with 99mTc-VIP are promising and warrant further study.

Topics: Adult; Feasibility Studies; Female; Humans; Isotope Labeling; Male; Middle Aged; Neoplasms; Oligopeptides; Radionuclide Imaging; Radiopharmaceuticals; Technetium; Time Factors; Vasoactive Intestinal Peptide

Topics: Animals; Apoptosis; Brain; Cell Death; Cytokines; Humans; In Vitro Techniques; Inflammation Mediators; Intestinal Mucosa; Lung; Lung Injury; Neoplasms; Neuroblastoma; Neurons; NF-kappa B; Nitric Oxide; Peptides; Rats; Signal Transduction; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc-99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc-99m-MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc-99m-TP 3654 (specific activity 11.3 x 10(3) Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc-99m-TP 3654, but not with Tc-99m-MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors.

Topics: Adenocarcinoma; Adult; Amino Acid Sequence; Autoradiography; Bone Neoplasms; Breast Neoplasms; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Neoplasms; Organotechnetium Compounds; Osteosarcoma; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Vasoactive Intestinal Peptide; Technetium Tc 99m Sestamibi; Vasoactive Intestinal Peptide

Antagonistic analogs of growth hormone-releasing hormone (GHRH) inhibit growth of various human cancers both in vivo and in vitro. GHRH, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide stimulate cyclic AMP (cAMP) release from various human cancer cell lines in vitro. Thus, in the present study, we investigated the effects of antagonistic analogs of GHRH on the GHRH- and VIP-induced cAMP release from cultured human cancer cells in a superfusion system. Various human cancer cell lines were exposed to human GHRH(1-29)NH2 (2-20 nM) or VIP (0.1-5 nM) repeatedly for 12 min or continuously for 96 min. GHRH antagonist MZ-5-156 at 100 to 200 nM concentration inhibited the GHRH- or VIP-induced cAMP release from mammary (MDA-MB-468), prostatic (PC-3), and pancreatic (SW-1990 and CAPAN-2) cancer cells. These results show that antagonistic analogs of GHRH suppress the stimulatory effects of GHRH and VIP on the cAMP production of various cancer cells. Because cAMP is a potent second messenger controlling many intracellular functions, including the stimulation of cell growth, an inhibition of autocrine/paracrine action of GHRH by the GHRH antagonists may provide the basis for the development of new methods for cancer treatment.

Topics: Animals; Breast Neoplasms; Cell Division; Cyclic AMP; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; In Vitro Techniques; Male; Neoplasms; Pancreatic Neoplasms; Pituitary Gland, Anterior; Prostatic Neoplasms; Rats; Second Messenger Systems; Sermorelin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

In vitro receptor measurements in tumors were performed to evaluate the potential of the vasoactive intestinal peptide receptor (VIP-R) as an imaging tool in human cancer.. Three hundred thirty-nine human tumors were investigated for their VIP-R content by in vitro receptor autoradiography on tissue sections with 125I-VIP. For comparison, somatostatin receptors (SS-R) were measured in adjacent sections of these tumors with 125I-[Tyr3]-octreotide.. VIP-R were characterized and localized in the neoplastic cells of most breast carcinomas, breast cancer metastases, ovarian adenocarcinomas, endometrial carcinomas, prostate cancer metastases, bladder carcinomas, colonic adenocarcinomas, pancreatic adenocarcinomas, gastrointestinal squamous cell carcinomas, non-small-cell lung cancers, lymphomas, astrocytomas, glioblastomas and meningiomas. Among neuroendocrine tumors, all differentiated and one-half of undifferentiated gastroenteropancreatic tumors, pheochromocytomas, small-cell lung cancers, neuroblastomas and inactive pituitary adenomas were found to express VIP-R. In general, VIP-R were found much more frequently than SS-R, but only 5 of 19 growth hormone-producing adenomas and no medullary thyroid carcinomas or Ewing sarcomas had VIP-R. In all tumors tested, the VIP-R were of high affinity and specific for VIP and pituitary adenylate cyclase-activating peptide. No cross-competition between VIP and SS could be identified.. Most human carcinomas express VIP-R, as measured by in vitro receptor autoradiography. These data represent the molecular basis for evaluation of VIP-R imaging of these tumors in vivo and predict its great potential value.

Topics: Autoradiography; Female; Humans; Image Processing, Computer-Assisted; In Vitro Techniques; Iodine Radioisotopes; Male; Neoplasms; Octreotide; Radionuclide Imaging; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase activating polypeptide (PACAP) is a newly discovered neuropeptide which exists in two biologically active forms: PACAP-38 consisting of 38 amino acids and PACAP-27, a peptide corresponding to the N-terminal 27 amino acids of PACAP-38. Both PACAPs are derived from a 176 amino acid precursor (preproPACAP) which in addition gives rise to a 29 amino acid peptide, designated PACAP-related peptide (PRP). The presence of the three preproPACAP-derived peptides (PACAP-38, PACAP-27 and PRP) in tumour tissue from nine patients with VIP-producing tumours (pancreatic carcinoma, neuroblastoma, ganglioneuroma and pheochromocytoma) and eleven patients with non-VIP-secreting tumours (gastrinoma, glucagonoma, somatostatinoma, neuroblastoma) was examined by specific radioimmunoassays. In seven out of the nine VIP-secreting tumours elevated concentrations of all the three preproPACAP-derived peptides were found compared with normal tissue, while the concentrations in the non-VIP-secreting tumours were within the normal range. PACAP-38 was in all cases the dominating peptide, the concentration ranging from 41 to 3606 pmol/g. When tumour extracts were fractionated on Sephadex G50 column, tricine gel electrophoresis or reverse-phase HPLC immunoreactive components corresponding to synthetic PACAP-38, PACAP-27 and human PRP were identified, suggesting that preproPACAP was fully processed. Immunocytochemical examination showed PACAP-immunoreactive cells in the tumour tissue which also stained for VIP. This co-localization of PACAP and VIP was confirmed by double-staining experiments on the same sections, demonstrating PHM/VIP mRNA and PACAP-immunostaining in the same cells.

Topics: Adrenal Gland Neoplasms; Ganglioneuroma; Humans; Neoplasms; Neuroblastoma; Neuropeptides; Neurotransmitter Agents; Pancreatic Neoplasms; Pheochromocytoma; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Precursors; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of 123I-labeled VIP and 123I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of 123I-labeled VIP binding to intact A431 cells was VIP [concentration causing half-maximal inhibition (IC50) = 2.9 +/- 1.9 (SD) nM] > OCT (IC50 = 9.3 +/- 1.7 nM) = SST > substance P = secretin (IC50 = 1 microM). Binding of 123I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by OCT = Tyr-3-OCT (IC50 = 1.5 +/- 0.3 nM) = SST > VIP (IC50 = 4.9 +/- 1.1 nM). This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [3H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC50 values < 10 nM. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.

Topics: Adenosine Triphosphate; Binding, Competitive; Blood Platelets; Cell Membrane; Cross Reactions; Cyclic AMP; Drug Interactions; Humans; Ligands; Mast Cells; Neoplasms; Neoplasms, Experimental; Neutrophils; Phosphorus Radioisotopes; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Somatostatin; Thymidine; Tritium; Tumor Cells, Cultured; 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

Topics: Diarrhea; Humans; Neoplasms; Vasoactive Intestinal Peptide

Topics: Achlorhydria; APUD Cells; Apudoma; Carcinoid Tumor; Carcinoma; Cholecystokinin; Diarrhea; Endocrine System Diseases; Humans; Hypokalemia; Malignant Carcinoid Syndrome; Neoplasms; Pancreatic Diseases; Paraganglioma; Paraneoplastic Endocrine Syndromes; Peptides; Prostaglandins E; Somatostatin; Syndrome; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Evidence that VIP is the principal humoral mediator of the watery diarrhea syndrome includes: (a) actions of VIP in experimental anaimals parallel the clinical manifestations of the syndrome; (b) infusions of VIP induce watery diarrhea in intestinal loops of dogs and a picture resembling the clinical syndrome in pigs, at circulating levels of the peptide similar to those observed in human disease; (c) most patients with the watery diarrhea syndrome and underlying tumors have elevated plasma levels of VIP; (d) in those patients in whom pre- and postoperative measurements were made, plasma VIP levels fell to the normal range with removal of the tumor and relief of the diarrhea; and (e) extracts of such tumors are rich in VIP-immunoreactivity and VIP-like biologic activity. A few patients with the syndrome have been reported to have normal plasma VIP levels, and it is possible that other humoral agents (such as pancreatic polypeptide, prostaglandins) may contribute to the production of the diarrhea.

Topics: Adenocarcinoma; Adenoma; Adenoma, Islet Cell; Animals; Diarrhea; Dogs; Gastrointestinal Hormones; Humans; Neoplasms; Pancreatic Neoplasms; Swine; Syndrome; Vasoactive Intestinal Peptide

Topics: Animals; Diarrhea; Gastrointestinal Hormones; Humans; Neoplasms; Swine; Syndrome; Vasoactive Intestinal Peptide

Topics: Animals; Congresses as Topic; Endocrine System Diseases; Gastric Inhibitory Polypeptide; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Motility; Glucagon-Like Peptides; Histamine; Humans; Insulin; Insulin Secretion; Motilin; Neoplasms; Neurotransmitter Agents; Pancreatic Hormones; Pancreatic Juice; Pancreatic Polypeptide; Secretin; Somatostatin; Vasoactive Intestinal Peptide

Topics: Brain Neoplasms; Calcitonin; Cholesterol; Diarrhea; Endocrine Glands; Gastrins; Gastrointestinal Hormones; Histamine Release; Humans; Hypercalcemia; Neoplasms; Nutrition Disorders; Pellagra; Peptides; Serum Albumin; Thyroid Hormones; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome