Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor receptors play critical roles in cancer cell proliferation and progression. A number of such receptors have been targeted for cancer treatment by either a monoclonal antibody or a specifically designed small molecule to inhibit the receptor function. Bombesin/gastrin-releasing peptide receptors (BN/GRP-Rs) are expressed in a variety of cancer cells and have limited distribution in normal human tissue. Inhibition of BN/GRP-Rs has been shown to block small cell lung cancer growth in vitro. Early phase clinical trials targeting human GRP-R showed anti-cancer activity. This review will focus on the study of the distribution of BN/GRP-Rs in normal and malignant tissues, and various approaches to targeting BN-GRP-Rs for cancer diagnosis and treatment.
 ...
PMID:Targeting gastrin-releasing peptide receptors for cancer treatment. 1551 61

Effects of in vivo treatment with antagonists of growth hormone-releasing hormone (GHRH), JV-1-65 and MZ-J-7-110, and bombesin/gastrin-releasing peptide antagonist RC-3940-II, on the EGF receptor (EGFR) family, were investigated in H-69 SCLC. Tumors were analyzed by RT-PCR, immunoblotting and binding assays. Treatment with these analogs reduced the binding capacity of EGFR by 18-64%, and inhibited the mRNA expression for EGFR, HER-2 and -3 by 27-75.4, 17-26.3, and 13.8-46.6%, respectively. The antagonists also decreased the protein levels for EGFR by 21-34%, HER-2 by 36-68% and HER-3 by 43-49%. This is the first demonstration that antiproliferative effects of GHRH antagonists are associated with a downregulation of EGF/HER receptors.
 ...
PMID:Antagonists of growth hormone releasing hormone and bombesin inhibit the expression of EGF/HER receptor family in H-69 small cell lung carcinoma. 1603 52

Small cell lung cancer (SCLC) patients suffer from pulmonary stresses such as dyspnea and chest pain, and the pathogenic mechanisms are not known. SCLC cells secrete a variety of bioactive neuropeptides, including bombesin-like peptides. We hypothesize that these peptides may enhance the sensitivity of the pulmonary chemosensitive nerve endings, contributing to the development of these pulmonary stresses in SCLC patients. This study was therefore carried out to determine the effects of bombesin and gastrin-releasing peptide (GRP), a major bombesin-like peptide, on the sensitivities of pulmonary chemoreflex and isolated pulmonary vagal chemosensitive neurons. In anesthetized, spontaneously breathing rats, intravenous infusion of bombesin or GRP significantly amplified the pulmonary chemoreflex responses to chemical stimulants such as capsaicin and ATP. The enhanced responses were completely abolished by perineural capsaicin treatment of both cervical vagi, suggesting the involvement of pulmonary C-fiber afferents. In isolated pulmonary vagal chemosensitive neurons, pretreatment with bombesin or GRP potentiated the capsaicin-induced Ca(2+) transient. This sensitizing effect was further demonstrated in patch-clamp recording studies; the sensitivities of these neurons to both chemical (capsaicin and ATP) and electrical stimuli were significantly enhanced by the presence of either bombesin or GRP. In summary, our results have demonstrated that bombesin and GRP upregulate the pulmonary chemoreflex sensitivity in vivo and the excitability of isolated pulmonary chemosensitive neurons in vitro.
 ...
PMID:Sensitization of pulmonary chemosensitive neurons by bombesin-like peptides in rats. 1604 Jun 30

Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor having sequence homologies to gastrin-releasing peptide and neuromedin B receptors. [d-Phe6, beta-Ala11, Phe13, Nle14]bombesin(6-14) is known to act as a synthetic receptor agonist for BRS-3. To characterize BRS-3-mediated biological responses, we examined the effect of BRS-3 activation by [d-Phe6, beta-Ala11, Phe13, Nle14]Bn(6-14) on the adhesion of the small cell lung cancer NCI-N417 cells that express native BRS-3. We found that the BRS-3 agonist stimulated adhesion of NCI-N417 cells in laminin-coated culture wells. The adhesion of the cells to laminin induced by BRS-3 activation was accompanied by an increase in vinculin-like immunoreactivity and diminished in the presence of an anti-beta1 integrin antibody, suggesting that the receptor activation stimulates focal adhesion formation. We suggest that BRS-3 may be involved in invasion and metastasis of certain cancer cells, like small cell lung cancer cells, upon attachment to laminin.
 ...
PMID:Activation of bombesin receptor subtype-3 stimulates adhesion of lung cancer cells. 1697 89

Progastrin-releasing peptide (proGRP) is a precursor of gastrin-releasing peptide, a hormone which is secreted from neuroendocrine cells. It has been shown to be a useful serum marker for small cell lung cancer. We raised monoclonal antibodies (MAbs) against proGRP with the primary aim of establishing a sensitive immunoassay. Immunization was performed with recombinant proGRP (amino acids 31-98) conjugated to thyroglobulin or with a DNP-modified peptide. Seven of the MAbs recognizing both recombinant and cell line-derived peptide were characterized and epitope-mapped. Based on cross-inhibition studies the antibodies could be categorized into three main groups. The molecular epitope assignment was studied by using phages displaying proGRP peptides, random peptide libraries displayed on phage and by pepscan analysis utilizing 10-mer biotinylated peptides. Two of the MAbs (E146, E172) bound to a defined region on the N-terminal part of proGRP(31-98), three recognized conformational-dependent epitopes in the middle of the peptide (E179, E180, E181) and two bound to the C-terminal part (E149, E168). Consensus sequences were obtained for MAbs E146, E149 and E168. The binding kinetics of the MAbs was determined by surface plasmon resonance, and a time-resolved immunofluorometric assay was established.
 ...
PMID:Production and Characterization of Monoclonal Antibodies for Immunoassay of the Lung Cancer Marker proGRP. 1728 11

Small cell lung cancer is a rapidly growing neoplasm with high mortality. A recently discovered biomarker, pro-gastrin-releasing peptide (ProGRP), is used as a specific diagnostic marker for the disease. The present methods of quantification are based on the immunoassay techniques RIA and ELISA. Our object was to develop an LC-MS method for the detection and quantification of ProGRP using specific tryptic digestion products from the recombinant peptide ProGRP (31-98), a sequence common to three isoforms of ProGRP. The conditions for enzymatic cleavage were optimized and MS compatibility was obtained. Digestion of ProGRP (31-98) yielded an array of peptide products and these were evaluated for further method development. The peptide product NLLGLIEAK proved to be the preferable candidate to monitor ProGRP due to signal intensity, column retention, and peptide specificity. The identity of this product was verified by means of LC-MS/MS and the linearity of the calibration curve evaluated. LOD was calculated to be 13.9 pg on column (O.C.). Plasma samples spiked with ProGRP (31-98) prior to digestion verified the suitability of this digest product for the determination of ProGRP. LC-MS may prove to be a valuable tool for biomarker mediated diagnosis in the future.
 ...
PMID:Determination of the small cell lung cancer associated biomarker pro-gastrin-releasing peptide (ProGRP) using LC-MS. 1739 Jun 17

Pro-gastrin-releasing peptide (ProGRP) is used as a specific diagnostic marker for small cell lung cancer (SCLC), a rapidly growing neoplasm with high mortality. Our object was to develop an LC-MS method for the detection and quantification of ProGRP in human serum using the specific tryptic digestion product NLLGLIEAK (m/z 485.8 for [M + 2H](2+)). For this purpose the sample pretreatment, clean-up, enrichment, and LC-MS conditions were evaluated. Sample pretreatment was carried out using ACN precipitation to decrease the sample complexity. Although ProGRP (31-98) standards were soluble in 99% ACN, it showed that optimal signal intensities were obtained by adding ACN to the serum in a 1:1 ratio v/v. A simplified tryptic digest protocol was carried out using 100 mM triethanolamine buffer to ensure pH stability during the whole procedure. The simplified protocol also includes omission of reducing and alkylating reagents. Necessary additional sample clean-up was achieved by trapping NLLGLIEAK on a RAM column (ADS-C8) which was back-flushed onto the analytical BioBasic C8 column. Volume of injection, sample enrichment, and column capacity are among the factors optimized to reach a mass LOD of 150 pg on column (OC) ProGRP (31-98). Detection of ProGRP in the serum sample of a patient suffering from SCLC with a clinically relevant concentration shows the potential of the method in diagnosis, prognosis, and monitoring of the disease.
 ...
PMID:Targeted determination of the early stage SCLC specific biomarker pro-gastrin-releasing peptide (ProGRP) at clinical concentration levels in human serum using LC-MS. 1787 17

Neuropeptide hormones like bombesin/gastrin-releasing peptide, galanin or bradykinin, acting via auto and paracrine growth loops, represent the principal mitogens of small cell lung cancer (SCLC). These mitogenic neuropeptides activate G(q/11)-coupled receptors which stimulate phospholipase Cbeta activity, followed by rises of the intracellular calcium concentration ([Ca2+](i)) and activation of protein kinase C (PKC). We report here that proline-rich tyrosine kinase Pyk2 is highly expressed in SCLC cells and provides a functional link between neuropeptide-induced increases in [Ca2+](i) and tumor cell proliferation. Activation of Pyk2 and its association with Src kinases critically depends on the elevation of [Ca2+](i), but is independent of PKC. Src kinase activities are crucial for neuropeptide-mediated GTP-loading of Ras and activation of extracellular signal-regulated kinases in SCLC cells. Pyk2 and Src kinases essentially contribute to anchorage-independent proliferation of SCLC cells. Inhibition of either Pyk2 or Src kinases by lentiviral RNAi or pharmacological inhibition with PP2, respectively, attenuated basal and neuropeptide-elicited survival and proliferation of SCLC cells in liquid culture and in soft agar. Thus, neuropeptides stimulate anchorage-independent survival and proliferation of SCLC cells via pathways involving Pyk2 and Src kinases. Therefore, Ca2+-induced Pyk2/Src complex formation may be a rewarding molecular target for novel therapeutic strategies in SCLC cells.
 ...
PMID:Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells. 1790 99

The usefulness of serum pro-gastrin-releasing peptide (ProGRP) as a tumor marker in patients with small cell lung cancer has recently drawn the attention of many research centers. The aim of the study was the evaluation of ProGRP, neuron-specific enolase (NSE), soluble fragment of cytokeratin 19 (CYFRA 21-1) and lactate dehydrogenase (LDH) levels at the time of diagnosis and during chemo- and radiotherapy of small cell lung cancer patients with limited disease (SCLC-LD). The studies were performed on a group of 64 patients with SCLC-LD who had received no prior therapy. All the patients were given the same treatment regimen. ProGRP, NSE, CYFRA 21-1 and LDH were measured before each course of chemotherapy and then at 3 and 6 months after the end of treatment. Prior to therapy, elevated levels of ProGRP, NSE, CYFRA 21-1 and LDH were found in 79.7%, 57.8%, 23.4%, and 12.5% of the patients respectively. Before the second chemotherapy course, all the tumor marker levels except LDH decreased significantly in comparison with the pretreatment concentrations. However, only ProGRP levels showed a progressive drop during consecutive courses of therapy, while NSE and CYFRA 21-1 fluctuated within reference ranges. When the study group was divided with respect to the effect of treatment evaluated six months from its termination, significant differences in ProGRP levels were found between both subgroups throughout all therapy and follow-up, except for the fifth course of chemotherapy. Differences in NSE levels were only significant for the first two courses and follow-up. Univariate analysis showed significant relationships between disease-free survival and the initial levels of NSE and CYFRA 21-1 as well as between overall survival and prophylactic cranial irradiation (PCI) and the initial ProGRP, NSE and CYFRA 21-1 levels. Changes of ProGRP level seem to be more precise than NSE as a tool for monitoring therapy in SCLC patients with limited disease, but for prediction of relapse, in addition to NSE determinations of ProGRP seem to be optimal.
 ...
PMID:ProGRP and NSE in therapy monitoring in patients with small cell lung cancer. 1903 51

All forms of the neuropeptide gastrin-releasing peptide (GRP) are derived from the precursor proGRP1-125. Amidated GRP18-27, which together with amidated GRP1-27 was long thought to be the only biologically relevant product of the GRP gene, is involved in a multitude of physiological functions and acts as a mitogen, morphogen, and proangiogenic factor in certain cancers. Recently, GRP has been implicated in several psychiatric conditions, in the maintenance of circadian rhythm, in spinal transmission of the itch sensation, and in inflammation and wound repair. The actions of GRP are mediated by the GRP receptor. Over the last decade, nonamidated peptides derived from proGRP, such as the glycine-extended form GRP18-28 and recombinant and synthetic fragments from proGRP31-125, have been shown to be biologically active in a range of tissues and in cancer cell lines. While GRP18-28 acts via the GRP receptor, the identity of the receptor for proGRP31-125 and its fragments has not yet been established. Nonamidated fragments are also present in normal tissues and in various cancers. In fact, proGRP31-98 is the most sensitive serum biomarker in patients with small cell lung cancer and is a significant predictor of poor survival in patients with advanced prostate cancer.
 ...
PMID:Gastrin-releasing peptide: different forms, different functions. 1931 48


<< Previous 1 2 3 4 5 6 7 Next >>