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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrin-releasing peptide (GRP) is a neuroendocrine hormone that may be involved in the pathophysiology of small cell lung carcinoma. We describe carboxylterminal peptide analogues of GRP and bombesin, a 14-residue amphibian homologue, that were modeled after the antagonist [Leu13-psi(CH2NH)-Leu14]bombesin and retained the psi bond. Three novel peptides contained a Leu insertion amino to the psi bond, i.e. ... Leu13Leu14 psi X (residues numbered after bombesin) where X = LeuNH2 or norleucine-NH2). The Leu-insertion analogues behaved as pure partial agonists/antagonists when examined for the ability to stimulate [3H]thymidine incorporation into quiescent Swiss 3T3 cells (agonist activity) and to diminish the agonist response of GRP (antagonist activity). A time course of [3H]thymidine incorporation into quiescent cells indicated maximal incorporation at 20-h post-peptide addition for bombesin and GRP and a Leu-insertion peptide, but the extent of the incorporation for the Leu-insertion peptide was half that of GRP and bombesin. The agonist dose responses of the Leu-insertion peptides (EC50 values of 1-10 nM) paralleled GRP and bombesin, but the maximal response of the Leu-insertion peptides, even at concentrations as high as 10(-4) M, was half the maximal value of GRP or bombesin. High concentrations of the Leu-insertion peptides antagonized 10 nM GRP (a concentration that produced a near-maximal GRP response) yielding a response that was half the maximal value of GRP and equivalent to the maximal response of the Leu-insertion peptides alone. Analogues of the form ... Leu13 psi X behaved as complete antagonists. The KD values of the Leu-insertion peptides for competitive binding versus 125I-GRP (2-50 nM) were as potent as parent ... Leu14 agonists. Stability studies indicated that peptide potencies for both agonist and antagonist activities diminished upon peptide incubation in medium or on cells. The results suggested that, for the Leu-insertion peptides, degradation into distinct products with different activities was not responsible for their partial agonist/antagonist behavior. Computer-generated molecular modeling studies indicated that the novel structures could adopt energy minimized conformations for either an agonist or an antagonist as proposed earlier (Coy, D.H., Heinz-Erian, P., Jiang, N.-Y., Sasaki, Y., Taylor, J., Moreau, J.-P., Wolfrey, W.T., Gardner, J.D., and Jensen, R. T. (1988) J. Biol. Chem. 263, 5056-5060).
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PMID:Conveyance of partial agonism/antagonism to bombesin/gastrin-releasing peptide analogues on Swiss 3T3 cells by a carboxyl-terminal leucine insertion. 140 Apr 23

Bombesin (BN)-like peptides (such as GRP, gastrin-releasing peptide) are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. The present paper deals with a new class of bombesin analogues carrying a nitrogen mustard at their N-terminus. Due to the irreversible binding to the BN receptor(s), these peptides eventually block the mitogenic effects of the natural ligand(s), regardless of their intrinsic "agonistic" or "antagonistic" structures. In Swiss 3T3 fibroblasts they inhibit [125I]GRP binding in the nanomolar/micromolar range. According to their "agonistic" or "antagonistic" structural features, they do or do not induce [3H]thymidine incorporation and p 115 phosphorylation. In competition experiments, alkylating "antagonists" selectively inhibit BN-induced thymidine incorporation either when given simultaneously with or 24 hours before the BN challenge. Alkylating "agonists" display antagonistic effects only in the sequential treatment.
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PMID:Bombesin receptor antagonists. 3. Irreversible alkylating analogues: melphalan derivatives. 166 60

The mammalian bombesin-like peptides gastrin-releasing peptide (GRP) and neuromedin B regulate numerous and varied cell physiologic processes in various cell types and have also been implicated as autocrine growth factors influencing the pathogenesis and progression of human small cell lung carcinomas. We report here the molecular characterization of the bombesin/GRP receptor. Structural analysis of cDNA clones isolated from Swiss 3T3 murine embryonal fibroblasts shows that the GRP receptor is a member of the guanine nucleotide binding protein-coupled receptor superfamily with seven predicted hydrophobic transmembrane domains. In vitro transcripts from cloned cDNA templates encompassing the predicted protein coding domain, when injected into Xenopus oocytes, resulted in expression of functional GRP receptors. The predicted amino acid sequence of the open reading frame in cDNA clones matches the amino-terminal sequence as well as the sequence of four tryptic fragments isolated from the purified protein. Expression of the GRP receptor cDNA in model systems potentially provides a powerful assay for the development of subtype-specific receptor antagonists that may prove to be of therapeutic importance in human small cell lung carcinoma.
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PMID:Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. 167 Nov 71

The tachykinin family of neuropeptides, including substance P and neurokinins A and B, induce a transient increase in intracellular free calcium concentration in human small cell lung carcinoma (SCLC) cells, as measured with a calcium indicator fura-2. The effects are dose dependent and even greater than that of bombesin at equimolar concentrations in these cells. The tachykinins, like bombesin, induce calcium mobilization mainly from intracellular store(s). None of the peptides, however, shows a stimulatory effect on DNA synthesis. In addition, exogenously applied bombesin does not stimulate DNA synthesis at any concentration tested. We also examined the effects of a recently reported bombesin antagonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P in SCLC cells, and compared them to those in Swiss 3T3 fibroblasts in which the mitogenic effect of bombesin is well characterized. The antagonist at 10(-5) M completely abolishes the Ca2+-mobilizing effect of 10(-7) M bombesin in SCLC cells, and that of 10(-9) M but not 10(-7) M bombesin in Swiss 3T3 cells. The antagonist at this concentration effectively inhibits the mitogenic action of bombesin (10(-9) M) in Swiss 3T3 cells; however, much higher doses (approximately 10(-4) M) are needed to inhibit DNA synthesis in SCLC cells. Moreover, the antagonist inhibits DNA synthesis in bombesin/gastrin-releasing peptide-nonproducing cells with a similar dose dependency as in producing cells. These results indicate that bombesin/gastrin-releasing peptide and other calcium mobilizing peptides do not always act as a growth factor in SCLC cells, and that the bombesin antagonist could inhibit growth of SCLC cells through a mechanism other than bombesin antagonism.
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PMID:Stimulation of calcium mobilization but not proliferation by bombesin and tachykinin neuropeptides in human small cell lung cancer cells. 168 10

In 17 cases of resected small cell carcinoma of the lung, there were 4 cases of central type and 13 cases of peripheral type. Histologic subtypes were classified into oat cell carcinoma (OAT), intermediate cell type (INT), and small cell carcinoma with large cell component (SC/LC). SC/LC was divided according to the criteria of Radice et al. Immunohistochemically, gastrin-releasing peptide (GRP) and neuron specific enolase (NSE) were used as markers for neuroendocrine cells, and keratin and secretory component (SC) were used as markers for epithelial and gland epithelial cells, respectively. Histologically, 4 cases of the central type were divided into 3 cases of INT and one case of SC/LC. Thirteen cases of the peripheral type were divided into 3 cases of OAT, 6 cases of INT, and 4 cases of SC/LC. SC/LC was more frequently seen in the peripheral type than in the central type. Immunohistochemically, there was no difference in the frequency of positive staining for GRP and NSE between the central and peripheral types, but positive staining for keratin and SC were more frequent in the peripheral type than in the central type. Three cases who survived more than 3 years were histologically divided into two cases of INT and one case of SC/LC. Immunohistochemically, these 3 cases showed positive staining for GRP or NSE, but also showed positive staining for keratin or SC. Our results showed that some of the peripheral type small cell carcinoma of the lung had histologic and immunohistochemical features which were different from those of typical small cell carcinoma. Long survival time after resection in some of the peripheral cases might be due to these features.
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PMID:[Central and peripheral type small cell carcinoma of the lung--histologic, immunohistochemical, and clinical analyses]. 169 98

The amphibian tetradecapeptide bombesin and its mammalian homolog gastrin-releasing peptide are neurotransmitters and paracrine hormones, and are mitogenic for fibroblast and small cell lung carcinoma cell lines. cDNAs encoding the bombesin/gastrin-releasing peptide receptor (BR) expressed by murine Swiss 3T3 fibroblasts were isolated using electrophysiological and luminometric Xenopus oocyte expression assays. Oocytes microinjected with BR transcripts responded to concentrations of bombesin from 1 x 10(-10) to 1 x 10(-6) M. These responses showed homologous desensitization and could be specifically blocked by bombesin antagonists. Sequence analysis showed that the BR has seven membrane-spanning domains and five potential N-linked glycosylation sites. Data base analysis showed that the BR is most homologous to the tachykinin receptors. Although tyrosine kinase activity has been associated with BR function, no tyrosine kinase homologies occur within the BR sequence.
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PMID:Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. 170 29

We tested whether Ca(2+)-mobilizing neuropeptides can function as growth factors for small cell lung carcinoma cells. The neuropeptides bradykinin, neurotensin, cholecystokinin, and vasopressin at nanomolar concentrations stimulated a rapid and transient increase in the intracellular concentration of Ca2+. Crucially, these peptides in the same concentration range also caused a marked increase in colony formation in semisolid medium in responsive small cell lung carcinoma cell lines. At optimal concentrations bradykinin, neurotensin, cholecystokinin, vasopressin, galanin, and gastrin-releasing peptide were equally effective in promoting clonal growth. These findings support the hypothesis that small cell lung carcinoma growth is sustained by an extensive network of autocrine and paracrine interactions involving multiple neuropeptides.
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PMID:Multiple neuropeptides stimulate clonal growth of small cell lung cancer: effects of bradykinin, vasopressin, cholecystokinin, galanin, and neurotensin. 171 14

We have previously described the neoplastic transformation of immortalized human bronchial epithelial cells (BEAS-2B) by the combination of the c-raf-1 and c-myc protooncogenes and the concomitant induction of neuron-specific enolase mRNA expression (A. Pfeifer et al., Proc. Natl. Acad. Sci. USA, 86: 10075-10079, 1989). In this paper we describe the morphological, biochemical, and immunohistochemical characteristics of the primary c-raf-1/c-myc tumors, xenografts of these tumors, and tumors that originated from cell lines of the primary neoplasm. The tumors were morphologically characterized by the appearance of desmosomes and tonofilaments, microvilli, and dense core granules representing markers of squamous, glandular, and neuroendocrine differentiation, respectively. A total of 11 of 13 tumors were positive by immunohistochemical techniques for neuron-specific enolase, serotonin (nine of 13), and calcitonin (six of 13). Keratins were expressed in 11 of 13 tumors, and while specific keratins (K5, K7, K16/K17) decreased, there was an increase of vimentin in the tumor cells. Gastrin-releasing peptide immunoreactivity was detectable in a small number of tumors (five of 13). BEAS-2B cells transfected with the c-raf-1 and c-myc protooncogenes and cell lines established from the primary tumors expressed major histocompatibility Class II antigen which has been found on small cell lung carcinoma cells. The tumors induced by the c-raf-1 and c-myc protooncogenes resemble the multidifferentiated phenotype of small cell lung cancer frequently detected in vivo and present a defined model to study the relation between molecular markers, phenotypical appearance, and response to chemotherapeutic agents and radiation.
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PMID:Human bronchial epithelial cells transformed by the c-raf-1 and c-myc protooncogenes induce multidifferentiated carcinomas in nude mice: a model for lung carcinogenesis. 171 50

Purification of the gastrin-releasing peptide (GRP) or bombesin receptor has proved elusive in part due to technical difficulties. In the present studies, the problem of oxidized radioligand was avoided by the use of 125I-GRP, which was verified to be not oxidized by high performance liquid chromatography. Specific 125I-GRP binding (at 0 degrees C) to intact human small cell lung carcinoma NCI-H345 cells which had been subjected to a dilute acid wash was 6 fmol/10(6) cells. Inhibition of GRP degradation by human H345 cell membranes through the use of phenanthroline or phosphoramidon permitted the development of binding assays for the GRP receptor in detergent-solubilized crude membrane preparations. The solubilized GRP receptor exhibited saturable, high affinity (KD = 1.3 nM), temperature-dependent specific binding averaging 402 +/- 65 fmol/mg protein (mean +/- S.E. for eight separate membrane preparations with 125I-GRP concentration = 3 nM), with a Bmax = 434 fmol/mg protein using a gel filtration binding assay. That the GRP receptor had been solubilized was demonstrated by its failure to pellet when centrifuged at 100,000 x g for 60 min, its passage through a 0.22-micron filter without loss of binding activity, and its elution in the void volume of a Sephadex G-50 gel filtration column, but within the inclusion volume of a Sephacryl S-200 column (Ve/V0 = 1.1). Isolation of the GRP receptor from human H345 cell-solubilized membranes was achieved by ligand affinity chromatography. A unique 70-kDa band on silver-stained reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis was reproducibly eluted from GRP14-27 affinity columns by an acidic high salt buffer, but binding activity was denatured by these conditions. The protein nature of the GRP receptor was demonstrated by its sensitivity to proteases after isolation. In addition, two unique bands of 65 and 70 kDa were eluted from the GRP14-27 affinity column with GRP14-27 in neutral buffer, and this eluate possessed specific 125I-GRP binding with a stoichiometry of approximately 1:1. Thus, reported here is the isolation of a functional membrane-associated, saturable, high affinity GRP receptor with temperature-dependent binding from the solubilized membranes of human H345 cells.
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PMID:Isolation of the bombesin/gastrin-releasing peptide receptor from human small cell lung carcinoma NCI-H345 cells. 185 48

Recent progress in cancer research revealed that gut hormones have the activity to regulate the cellular growth of cancer cells. Gastrin, cholecystokinin and vasoactive intestinal peptide were demonstrated to stimulate the growth of gastric cancer cells, pancreatic cancer cells and colon cancer cells, respectively. Accordingly, it is possible to assume that these gut hormones may play an important role in the progression of these cancers. Further studies will be required to clarify the role of gut hormones as physiological growth factors in gastrointestinal tissues. The other aspect of gut hormones related with cellular growth is their role as autocrine growth factors. Gastrin-releasing peptide (GRP) is classified as a gut hormone with the structural similarity with amphibian bombesin. Several reported findings indicate that GRP functions as an autocrine growth factor for human small cell lung carcinoma; a monoclonal antibody for GRP is now applied for the therapy of this cancer. It is important to find out other gut hormones functioning as autocrine growth factors.
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PMID:[Gut hormones with activity to modulate cellular growth]. 208 20


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