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)

Previously, gastrin-releasing peptide (GRP) receptors were identified on small-cell lung cancer (SCLC) cells and GRP functioned as a SCLC autocrine growth factor. Here the effects of neuromedin B (NMB) on SCLC cells were investigated. [125I-Tyr0]NMB bound with high affinity to three of seven SCLC cell lines examined. [125I-Tyr0]NMB bound to SCLC cell line NCI-H209 and NCI-H345 in a time-dependent and reversible manner. [125I-Tyr0]NMB bound with high affinity (Kd = 1 nM) to a single class of sites (Bmax = 800/cell). Specific [125I-Tyr0]NMB binding was inhibited with high affinity by NMB (IC50 = 1 nM) and moderate affinity by bombesin, GRP and [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P ([APTTL]SP) but not GRP1-16 (IC50 = 50, 100, 1,000 and > 10,000 nM, respectively). In Fura 2 AM loaded NCI-H345 cells, NMB elevated cytosolic calcium in a concentration-dependent manner. NMB (10 nM) elevated the cytosolic calcium from 150 to 180 nM and calcium was released from intracellular pools. The increase in cytosolic calcium caused by 10 nM NMB was reversed by 1 microM [APTTL]SP but not 1 microM [D-Phe6]bombesin6-13methylester, a GRP receptor antagonist. Also, NMB stimulated the clonal growth of NCI-H209 and NCI-H345 in a concentration-dependent manner. The increase in the clonal growth caused by NMB was reversed by 1 microM [APTTL]SP. These data suggest that NMB receptors may regulate the proliferation of some SCLC cells.
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PMID:Neuromedin B binds with high affinity, elevates cytosolic calcium and stimulates the growth of small-cell lung cancer cell lines. 132 11

Tachykinins produce concentration-dependent contraction of the human isolated bronchus by stimulation of receptors that belong to the NK2 type. The aim of this study was to investigate the inhibitory effects of a new, potent, and selective nonpeptide antagonist of the neurokinin A (NKA) (NK2) receptors, SR 48968 [(S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl]benzamide] on human isolated airways. Our experiments were performed on human isolated bronchi obtained from patients with lung cancer. Phosphoramidon, 10(-5) M, was added to the bath to inhibit neurokinin metabolism. SR 48968 induced a parallel shift to the right of the concentration-response (C/R) curves to [Nle10]-NKA(4-10), a specific NK2 receptor agonist. The antagonism was of the competitive type, with a pA2 of 9.40 +/- 0.19 (slope = 0.95 +/- 0.08, n = 13). The (R)-enantiomer of SR 48968 was 100-fold less potent and a noncompetitive antagonist (slope = 0.56 +/- 0.11, n = 8); pA2 and slope of the racemate were 8.86 +/- 0.21 and 1.09 +/- 0.21 (n = 7), respectively. Under similar conditions, racemic CP-96,345, a nonpeptide NK1 antagonist, did not modify the C/R curves to [Nle10]-NKA(4-10) until 10(-7) M. SR 48968 did not modify C/R curves to acetylcholine, histamine, KCI, or PGF2 alpha on the human isolated bronchus. Finally, SR 48968 shifted to the right C/R curves to substance P on isolated human bronchi, whereas racemic CP-96,345 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects on the isolated human bronchus of SR 48968, a potent and selective nonpeptide antagonist of the neurokinin A (NK2) receptors. 133 56

Mast cells and histamine-mediated reactions may be altered in patients with cancer. In an attempt to characterize the possible skin defects in patients with cancer, we tested 22 patients suffering from lung cancers, 30 from breast cancers, and 30 age-matched normal individuals, using several compounds, in investigating the pathophysiology of the skin response. Histamine hydrochloride (10 and 100 mg/ml) and codeine phosphate (9%) were tested by prick test. Substance P (50 and 500 ng per injection site), phentolamine (20 micrograms per injection site), and carbachol (1 microgram per injection site) were tested by intradermal skin tests. Skin mast cells were also microscopically examined in 10 patients with lung cancer, five with breast cancer, and 10 normal subjects. The mean wheal sizes induced by all the tested substances were similar in patients with cancer and chronic bronchitis and in normal individuals. The flare to histamine, codeine phosphate, and substance P was completely abolished in 7/22 patients with lung cancer, but the lack of flare was not related to the age of the patients, nor to the staging of cancer, nor to metastasis. The mean numbers of alcian blue-stained or toluidine blue-stained positive mast cells were similar in normal subjects and in subjects with cancer. This study does not confirm the skin hyporeactivity of patients with cancer.
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PMID:Skin test reactivity in patients suffering from lung and breast cancer. 171 Jun 31

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.
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PMID:Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P. 861 70

Exposure to nitrogen dioxide (NO2), a common oxidant airborne pollutant, has been shown to cause reversible effects on lung function and airway responsiveness, in addition to airways inflammation. However, there have been conflicting reports concerning NO2-induced airway hyperresponsiveness. In the present study, we investigated the isotonic smooth muscle response in isolated human bronchi previously exposed in vitro to NO2. Bronchial segments were obtained from 12 patients who had undergone thoracotomy for lung cancer. Bronchial segments from each patient were exposed to air and to 2.5 parts per million (ppm) NO2 for 4 h. The contractile response of bronchial rings to acetylcholine, neurokinin A (NKA), and substance P was then studied under isotonic conditions. The response to NKA was also studied in rings, with or without epithelium, exposed either to air or 7 ppm NO2. No NO2-induced alteration of the bronchial smooth muscle isotonic response was found under any of the experimental conditions. We conclude that in vitro exposure to up to 7 ppm nitrogen dioxide does not cause alterations of the human bronchial smooth muscle shortening capacity.
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PMID:Isotonic smooth muscle response in human bronchi exposed in vitro to nitrogen dioxide. 894 74

[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following i.p. administration at 12 micrograms/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P acid and [D-Arg1,D-Phe5,D-Trp7,9]substance P(1-10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 micrograms/g x min) and the lowest in the brain (5 micrograms/g x min). Uptake into the tumor xenograft was poor (AUC 189 micrograms/g x min); however, uptake into the lungs was much greater (AUC 507 micrograms/g x min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.
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PMID:Processing of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice. 935 69

[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) (antagonist G) is a novel class of anti-cancer agent that inhibits small-cell lung cancer (SCLC) cell growth in vitro and in vivo and is entering phase II clinical investigation for the treatment of SCLC. Although antagonist G blocks SCLC cell growth (IC50 = 24.5 +/- 1.5 and 38.5 +/- 1.5 microM for the H69 and H510 cell lines respectively), its exact mechanism of action is unclear. This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM). This activity is neuropeptide-independent, but dependent on the generation of reactive oxygen species (ROS) and is inhibited by the free radical scavenger n-acetyl cysteine. Furthermore, antagonist G itself induces inflammation (59% increase in oedema volume compared to control) and potentiates (by 35-40%) bradykinin-induced oedema formation in vivo. In view of these results we show that, as well as acting as a 'broad-spectrum' neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 +/- 12% stimulation at 10 microM), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins. This novel activity may be instrumental for full anti-cancer activity in SCLC cells and may also account for antagonist G activity in non-neuropeptide-dependent cancers.
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PMID:[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) activates JNK and induces apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism. 1036 11

[Arginine]vasopressin (AVP) is a neuropeptide physiologically synthesized in the hypothalamus but pathologically expressed by small-cell lung cancer (SCLC). A minimal 65 bp AVP promoter can restrict basal activity to SCLC in vitro, but a 199 bp fragment directs 5-fold higher expression in SCLC [Coulson, Stanley and Woll (1999) Br. J. Cancer 80, 1935-1944]. Several predicted E-box motifs occur within the 199 bp fragment, and we now describe an enhancer which contributes to AVP promoter tumour-specificity in some cell lines. The deletion of two adjacent E-boxes (-157 to -131) resulted in an approx. 70% loss of reporter gene expression in a SCLC line (Lu-165) with high endogenous AVP production. Using a series of AVP promoter deletion constructs and site-directed mutagenesis, we show that both these E-box sites were required for enhancer function, whereas mutation of an adjacent AP-1 site had no effect on the promoter activity. Electrophoretic-mobility-shift analysis indicated that, although both the predicted E-box motifs bound specific complexes, only one appeared to function as a strong E-box which binds basic helix-loop-helix (bHLH) factors. This motif formed a complex in lung tumour-cell extracts, which was particularly strongly bound in Lu-165, and was competed for by a characterized E-box motif from the preprotachykinin A promoter. Antibody supershifts indicate that this complex is a heterodimer of upstream stimulatory factor (USF)-1 and USF-2. Non-bHLH complexes weakly bound the second potential E-box motif in a SCLC-specific manner. These complexes were not recognized by the bHLH antibodies and remain unidentified; however, they were detected in seven of eight SCLC cell lines and not in four control lines. We postulate that there is a co-operative and complex interaction between an E-box and an adjacent site constituting a SCLC-specific enhancer within the AVP proximal promoter.
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PMID:E-box motifs within the human vasopressin gene promoter contribute to a major enhancer in small-cell lung cancer. 1058 87

A recently developed pyridine derivative, Y-27632, has been reported to inhibit smooth muscle contraction by inhibiting Ca(2+)sensitization in animal experiments. However, the effect of this compound in human tissues has not yet been elucidated. The aim of the present study was to evaluate the effect of Y-27632 on human bronchi and pulmonary arteries. The tissues were obtained from lung cancer patients undergoing lung resection. Tissue responses were assessed by isometric tension measurement. Y-27632 relaxed the bronchi at basal tone with an IC(50)(concentration causing 50% relaxation of the maximal response) of 2.0+/-0.3x10(-6)M. Y-27632 also dose-dependently relaxed the bronchi precontracted by acetylcholine (ACh), histamine and neurokinin A, and the IC(50)was 3.0+/-0.4x10(-6), 2.5+/-0.5x10(-6)and 1.8 +/-0.3x10(-6)M, respectively. The dilatory effect of Y-27632 was significantly smaller in ACh-precontracted tissues compared with those of basal or histamine- and neurokinin A-induced precontracted bronchi (P<0.05). Further, Y-27632 showed an inhibitory effect on cholinergic nerve stimulation- and ACh-induced bronchial contraction to the same degree, suggesting that a modulatory effect of this compound on ACh release from nerve terminals was unlikely. Y-27632 also dilated the pulmonary arteries precontracted by phenylephrine (IC(50)= 1.6+/-0.1x10(-6)M). These data suggest that Y-27632 has a dilatory capacity on human bronchi as well as on pulmonary arteries.
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PMID:Effect of a calcium sensitization modulator, Y-27632, on isolated human bronchus and pulmonary artery. 1071 87

A synthetic peptide, (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was used to investigate the signal transduction mechanisms of bombesin receptor subtype-3. Using NCI-1299#5 human lung cancer cells stably transfected with bombesin receptor subtype-3, 100 nM (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) elevated the cytosolic Ca2+ from 150 to 250 nM within 10 s. Addition of (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused phosphorylation of mitogen activated protein kinase in a time- and concentration-dependent manner. The mitogen activated protein kinase phosphorylation caused by (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by 2'-amino-3'-methyoxyflavone (PD98059), a mitogen activated protein kinase kinase (MEK-1) inhibitor. Using a luciferase reporter gene construct, (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused Elk-1 activation after 10 min and the increase in Elk-1 activation caused by (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059 as well as a dominant-negative MEK-1. (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused increased c-fos as well as c-jun mRNAs 1 h after addition to NCI-H1299#5 cells. The 47-fold increase in c-fos mRNA caused by 100 nM (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059, a dominant-negative MEK-1 and a substance P antagonist but not (3-phenylpropanoyl-D-Ala(24), Pro(26), Psi(26,27), Phe(27))GRP-(20-27) (BW2258U89), a GRP receptor antagonist. These results indicate that (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused increased nuclear oncogene expression and upstream events include mitogen activated protein kinase phosphorylation and Elk-1 activation.
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PMID:A bombesin receptor subtype-3 peptide increases nuclear oncogene expression in a MEK-1 dependent manner in human lung cancer cells. 1116 31


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