Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peptidergic/aminergic innervation of normal liver and tumour blood vessels was investigated in order to determine vascular control with a view to improving the efficacy of hepatic arterial cytotoxic infusion in the treatment of colorectal liver metastases. Selected areas of liver metastases and macroscopically normal liver from resection specimens (n = 13) were studied using light microscope immunohistochemistry for the presence of protein gene product 9.5 (PGP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP) and tyrosine hydroxylase (TH). The ultrastructure of blood vessels supplying liver metastases and their perivascular innervation were also examined by transmission electron microscopy. In the normal liver, perivascular immunoreactive nerve fibres containing PGP, NPY and TH were observed around the interlobular blood vessels and along the sinusoids and the central vein of the hepatic lobule. The greatest density of immunoreactive nerve fibres was seen for PGP, followed (in decreasing order) by NPY and TH. VIP, SP and CGRP immunoreactivity was observed only in nerve bundles associated with the large interlobular blood vessels. In contrast, no perivascular immunoreactive nerves were observed in colorectal liver metastases. Electron microscopy confirmed the absence of perivascular nerves in liver metastases. In addition, it showed that the walls of these blood vessels were composed of a layer of endothelial cells surrounded by an incomplete or, very rarely in the periphery of the tumour, a complete, layer of synthetic phenotype of smooth muscle-like cells. These results imply that the blood vessels supplying liver metastases are bereft of normal neuronal regulation; whether there is a role for endothelial cell control of blood flow in these vessels is not yet known.
Br J Cancer 1996 Feb
PMID:The absence of autonomic perivascular nerves in human colorectal liver metastases. 856 41

Broad-spectrum neuropeptide growth factor antagonists, such as [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.
Br J Cancer 1996 Mar
PMID:Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P. 861 70

The protein tyrosine kinase inhibitor [(3,4,5,-trihydroxyphenyl)-methylene]-propanedinitrile (tyrphostin) was originally designed to inhibit polypeptide growth factor receptor signalling, but was also found to inhibit neuropeptide stimulated tyrosine phosphorylation and mitogenesis in Swiss 3T3 cells [J Biol Chem 1993, 268, 9548-9554]. Here, we demonstrate that tyrphostin inhibits in vitro colony growth of the H-345 and H-69 small cell lung cancer (SCLC) cell lines stimulated by the neuropeptides, bombesin and bradykinin, respectively. This effect was dose-dependent and, at tyrphostin concentrations above 5 microM, both background and neuropeptide stimulated colony formation were reduced. In liquid culture, tyrphostin inhibited the growth of the H-345 and H-69 SCLC cell lines with an IC50 of 7 microM. Time course experiments in liquid culture revealed that tyrphostin delayed the rate of entry of both SCLC cell lines into rapid phase growth and reduced the number of cells reaching a plateau phase of growth compared with control cells. Furthermore, tyrphostin concentrations at or above 50 microM reduced the number of cells present over time compared with untreated cells. When combined with a substance P (SP) analogue, which inhibits the action of multiple neuropeptides and SCLC cell growth, both in semisolid media and liquid culture, tyrphostin additively inhibited the growth of the H-345 and H-69 SCLC cell lines in liquid culture.
Eur J Cancer 1996 Feb
PMID:Effect of tyrphostin combined with a substance P related antagonist on small cell lung cancer cell growth in vitro. 866 52

Small cell lung cancer (SCLC) cell growth is sustained by multiple autocrine and paracrine growth loops involving neuropeptides. The bombesin family of peptides are autocrine growth factors in H345 SCLC cells and provide a paradigm for the study of growth factors and mitogenic signaling in SCLC cells. We show that bombesin (and other neuropeptides) stimulates protein tyrosine phosphorylation (particularly focal adhesion kinase) and protein tyrosine kinase (PTK) activity in intact SCLC cells. Furthermore, the broad spectrum neuropeptide receptor antagonist [D-Arg, D = Phe, D-Trp, Leu11]substance P inhibits all neuropeptide-mediated signals (including PTK activation), SCLC cell growth in vivo and in vitro, and also increases the natural rate of apoptosis seen in growing SCLC cell lines. Hence the effect of selective PTK inhibition on SCLC cell growth and apoptosis was examined. We show that selective inhibition of PTK activity, with genistein and (3,4,5-tri-hydroxyphenyl)-methylene(-propanedinitrile) tyrphostin-25 inhibits basal and neuropeptide-stimulated SCLC cell growth. Genistein and tyrphostin-25 also stimulate apoptosis in SCLC cells. Inhibition of proliferation in these cells is intimately linke to apoptosis, because these changes occurred without any effect on SCLC cell cycle kinetics, suggesting that apoptosis occurs independently of the cell cycle and that failure to progress through the cell cycle results in apoptosis. Because tyrphostin-25 fails to influence p53 or Bcl-2 expression in these cells, this mode of programmed cell death appears to be via a p53- and Bcl-2-independent mechanism. These results provide evidence that tyrosine phosphorylation is a mitogenic signal in SCLC cells and suggest that regulation of the level of protein tyrosine phosphorylation represents a critical determinant of whether SCLC cells survive and proliferate or die by apoptosis. Thus PTK inhibition may provide a novel therapeutic option in SCLC that has become resistant to conventional chemotherapeutic agents.
Cancer Res 1996 Sep 15
PMID:Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. 879 1

The rationale for and efficacy of bisphosphonates for pain due to cancer that has metastasized to bone are reviewed. Typical strategies for controlling metastatic bone pain have consisted of opioids, nonsteroidal anti-inflammatory drugs, surgery to stabilize bone, cancer chemotherapy, radiation therapy, and radiopharmaceuticals. Cancer metastasis to bone can produce pain through the release of prostaglandins, bradykinin, substance P, and histamine; growth of tumor into surrounding tissue; stretching of the periosteum; and pathological fractures. It has been suggested that bisphosphonates can benefit these patients by decreasing the amount of pain or decreasing analgesic requirements. Bisphosphonates bind to hydroxyapatite crystals, making it more difficult for osteoclasts to recognize exposed unmineralized bone surfaces, and are directly toxic to osteoclasts. Etidronate disodium, pamidronate disodium, clodronate disodium, and alendronate sodium are bisphosphonates that have been studied in patients with painful bone metastases. Although each of these has shown at least some benefit, the most promising agent appears to be pamidronate, especially the i.v. formulation given monthly. Although oral formulations of this agent have been studied, poor bioavailability and adverse effects limit their usefulness. Adverse effects of bisphosphonates include GI reactions, impairment of renal function, anemia, and electrolyte abnormalities. Bisphosphonates are of some benefit in relieving metastatic bone pain, but the exact role, agent, route, and duration are issues that need further study.
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PMID:Bisphosphonates for controlling pain from metastatic bone disease. 886 2

The neuropeptide substance P (SP) regulates many biological processes through binding to and activating the SP receptor (NK-1 subtype). Activation of the SP receptor induces mitogenesis in several cell types. In this study, we characterized the mitogenic response induced by SP peptide in the U-373MG astrocytoma cell line and showed that activation of the SP receptor induces [3H]thymidine incorporation into DNA. We also found that SP potently induces c-myc mRNA and protein in the U-373MG cells. Tyrphostin A25, which blocks activity of tyrosine kinases, significantly inhibited SP-induced mitogenesis, suggesting that the mitogenic response induced by SP peptide involves phosphorylation by tyrosine kinases. Furthermore, stimulation of the SP receptor activates tyrosine phosphorylation and enzymatic activity of extracellular signal-regulated kinases (Erk1 and Erk2), also called the mitogen-activated protein kinases (MAPKs). This result suggests that MAPKs participate in the SP peptide-induced signaling pathway. The addition of CP 96,345 ([(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1 -azabicyclo[2.2.2]octan-3-amine]; an NK-1 receptor antagonist) or PD 098059 (MEK1 inhibitor) inhibited both DNA synthesis and activation of the MAPK pathway, substantiating that SP stimulates mitogenesis by activating the MAPK pathway through receptors of the NK-1 subtype. Our results demonstrate that SP peptide is a strong mitogen in the U-373MG astrocytoma cell line and establish a clear correlation between SP-induced mitogenesis and activation of MAPK signaling pathway.
Cancer Res 1996 Nov 01
PMID:Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated protein kinase signaling pathway. 889 54

Though antiemetic therapy has improved markedly in the past 15 years, patients still regard nausea and vomiting as two of the most distressing adverse events during chemotherapy. A major progress was the development of the serotonin3 (5-HT3) receptor antagonists. A possible antiemetic effect, achieved by interference with the "serotonergic system", is not restricted to antagonism at 5-HT3 receptors, however, but also includes agonism at 5-HT1A and 5-HT2 receptors, and serotonin synthesis inhibitors. The number of receptors thought to be involved in the emetic reflex has been augmented by neurokinin1 receptors with substance P as the preferred ligand. Animal studies have demonstrated a broad antiemetic profile of substance P antagonists. The somatostatin analogue octreotide has an antiemetic effect in patients with gastrointestinal obstruction, but has not been investigated against chemotherapy-induced emesis. The next few years will disclose, whether the efficacy and safety profiles of one or more of these drugs will make it clinically useful in the treatment of chemotherapy-induced nausea and vomiting.
Support Care Cancer 1996 Nov
PMID:New perspectives in antiemetic treatment. 896 71

[D-Arg1,D-Trp5,7,9,Leu11]Substance P (SP) was identified out of a panel of novel SP analogues as the most potent inhibitor of small cell lung cancer (SCLC) cell growth. This analogue inhibited proliferation of H-510 and H-69 SCLC cells in liquid culture and in semisolid media (IC50, 5 microM). Colony formation stimulated by multiple neuropeptides, including vasopressin and bradykinin, was also blocked by [D-Arg1,D-Trp5,7,9,Leu11]SP. This new SP analogue inhibited vasopressin- or bradykinin-induced Ca2+ mobilization and mitogen-activated protein kinase activation. Administration of [D-Arg1,D-Trp5,7,9,Leu11]SP inhibited the growth of an H-69 xenograft in nude mice. Our results support the hypothesis that SP analogue broad-spectrum neuropeptide antagonists could be of therapeutic value in SCLC.
Cancer Res 1997 Jan 01
PMID:[D-Arg1,D-Trp5,7,9,Leu11]substance P: a novel potent inhibitor of signal transduction and growth in vitro and in vivo in small cell lung cancer cells. 898 40

DAB389 GRP is composed of the catalytic and transmembrane domains of diphtheria toxin fused to gastrin-releasing peptide (GRP). DAB389 GRP is selectively targeted to, and inhibits protein synthesis in, cell lines expressing GRP receptors. Protein synthesis in 5'ET4 cells (BALB/3T3 fibroblasts transfected with the gene encoding the GRP receptor) was inhibited by 50% in the presence of 20 pM DAB389 GRP (IC50, 20 pM). DAB389 GRP did not inhibit protein synthesis in untransfected BALB/3T3 cells. A second neuropeptide-conjugated toxin, DAB389 SP, directed to cells expressing substance P receptors, was not cytotoxic to 5'ET4 cells, nor was DAB389 GRP cytotoxic to substance P receptor-bearing cells. DAB389 GRP cytotoxic effects were receptor specific and were inhibited either by excess GRP or anti-GRP antibody. Cytotoxicity was mediated by passage through an acidic vesicle, because addition of 10 microM chloroquine to the reaction inhibited cytotoxicity. DAB389 GRP and DAB389 SP were tested on a number of tumor cell lines. DAB389 GRP inhibited protein synthesis in AR42J rat pancreatic acinar cells and HuTu 80 human duodenal adenocarcinoma cells with IC50s of 65 and 200 pM, respectively. DAB389 SP had an IC50 of 9.5 pM for the AR42J cells and 12 nM for the HuTu 80 cell line. A number of small cell lung cancer cell (SCLC) lines were tested, and the IC50 for DAB389 GRP ranged from 1.1 to 85 nM. Sensitivity to DAB389 GRP appeared to be based on receptor number and receptor type (i.e., GRP or neuromedin B preferring). SCLC cells were also sensitive to DAB389 SP, with IC50s ranging from 2.4 to 11.5 nM. These results suggest that a potential use exists for diphtheria-based fusion toxins as therapeutic agents for treatment of SCLC and other neuropeptide receptor-bearing cancers.
Cancer Res 1997 Jan 15
PMID:Inhibition of protein synthesis in small cell lung cancer cells induced by the diphtheria toxin-related fusion protein DAB389 GRP. 900 May 70

We used antibodies to a number of neuromodulatory substances, including serotonin, FLRF amide, red pigment-concentrating hormone, substance P, proctolin and cholecystokinin, to investigate the distribution of molecules similar to these substances in the stomatogastric ganglion of the crab, Cancer borealis. No immunoreactivity was seen in the region of the cell bodies that surrounds the neuropil and little was found in the core of the neuropil (where the primary neurites of the intrinsic neurons occupy most of the space). Instead, modulator immunolabel was densely packed in the more peripheral portion of the neuropil that surrounded the core. Within this peripheral neuropil, profiles appeared quite uniformly distributed. Double-labeling showed that there were limited differences in distribution between the labels examined in our study. The only immunolabeled structures that showed a distinct differential distribution within the stomatogastric neuropil were a population of >/=10 microm varicosities that arose from a pair of input fibers that we termed the large varicosity fibers. These varicosities were immunolabelled by antisera for three different peptides. Taken collectively, these data shows that there is a stereotyped distribution of modulator immunoreactivity within the crab stomatogastric neuropil. However, this segregation is more rudimentary than that reported for the intrinsic stomatogastric neurons.
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PMID:Organization of the stomatogastric neuropil of the crab, Cancer borealis, as revealed by modulator immunocytochemistry. 904 81


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