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

Products of the gastrin-releasing peptide gene were isolated from culture medium supernatant of a small cell lung cancer line, NCI-H345, by several (high performance liquid chromatography) HPLC steps. The column eluates were monitored by immunoassay and absorbance profiles. Gastrin-releasing peptide was identified in HPLC eluates by a specific radioimmunoassay. Two carboxyl-terminal gastrin-releasing peptide gene-associated peptides were identified by a radioimmunoassay specific for their predicted carboxyl terminus. The amino termini of these two peptides were determined by microsequence analysis. The shorter peptide was revealed to be a fragment of the larger peptide. Expression of an alternate mRNA was shown by isolation and characterization of a novel tetradecapeptide. Amino acid analysis, microsequence analysis, and mass spectral analysis confirmed that the structure was Ser-Leu-Leu-Gln-Val-Leu-Asn-Val-Lys-Glu-Gly-Thr-Pro-Ser. This peptide represents the carboxyl terminus of a peptide resulting from alternate processing of gastrin releasing peptide mRNA. This mRNA contains a 19-base deletion, creating a frame shift. A radioiodinated synthetic analog of this peptide (Tyr-Leu-Val-Asp-Ser-Leu-Leu-Gln-Val-Leu-Asn-Val-Lys-Glu-Gly-Thr-Pro-Ser ) bound specifically to a small cell cancer line with high affinity, suggesting possible biological activity of the isolated peptide.
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PMID:Multiple gastrin-releasing peptide gene-associated peptides are produced by a human small cell lung cancer line. 253 94

A series of heptapeptide somatostatin (SRIF) analogs containing mercaptopropionic acid (Mpa) and based on the parent structure Mpa-Tyr-[D]Trp-Lys-Val-Cys-Thr-NH2 were synthesized by solid-phase methodologies and assayed for their effects on rat growth hormone (GH) secretion and their ability to displace [125I]Tyr11-SRIF bound to various tissues in vitro. Structural modifications consisted primarily of aromatic substitutions for Thr. All analogs were less potent than SRIF in inhibiting GH secretion in vitro from 4-day primary cultures of rat pituitary cells (0.04-21% that of SRIF). Higher GH inhibitory potencies were observed in an acute 15 min in vivo potency assay probably reflecting increases in plasma half-life of the analogs as compared to native SRIF. All analogs had extremely low binding affinity for rat cerebral cortex (0.05-4% that of SRIF), while binding potency for rat pancreas ranged from 3-130% of SRIF. Several analogs exhibited enhanced binding to human small cell lung carcinoma cells (SCLC; NCI-H69) as compared to SRIF. One of these, containing Phe at the C-terminus, exhibited an affinity 3.5 X greater than SRIF itself and was further tested for possible effects on the proliferation of SCLC and rat pancreatic tumor cells (AR42J) in vitro. The proliferation of both tumor types was inhibited 32 and 60%, respectively (p less than 0.01). The data suggest that SRIF and certain analogs may have a direct action on proliferating tumors independent of endocrine effects and that the anti-tumor activity of SRIF analogs can be further dissociated from the other actions of native SRIF, thereby providing for potentially more selective therapeutic analogs.
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PMID:Novel heptapeptide somatostatin analog displays anti-tumor activity independent of effects on growth hormone secretion. 257 97

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
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PMID:Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly. 624 40

Reverse transcription-PCR-single-strand conformation polymorphism analysis was performed to detect topoisomerase IIalpha mutations using total RNA from 19 bronchial biopsy specimens obtained from 13 patients with small cell lung cancer. An abnormally migrating single-strand conformation polymorphism band was observed in one tumor sample from a patient treated with etoposide-containing chemotherapy. DNA sequence analysis of this tumor showed two transversions at codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that previously found in two cell lines selected for amsacrine resistance. These results demonstrate that mutations of topoisomerase IIalpha occur in patients with small cell lung cancer. The significance of these mutations in the development of resistance to etoposide needs further investigation.
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PMID:Point mutations of the topoisomerase IIalpha gene in patients with small cell lung cancer treated with etoposide. 864 Aug 4

Actions of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; BK) are mediated by constitutively expressed B2 receptors (which require the full BK peptide chain) and by B1 receptors (which require BK (1-8) as ligand) that are induced in inflammation. BK has many functions in normal and pathological physiology, including initiation of most, if not all, inflammation. BK also evidently functions as an autocrine stimulant for growth of small cell lung cancer (SCLC). A new group of BK antagonists containing the novel amino acid alpha-(2-indanyl)glycine (Igl) provides both broad-spectrum and selective antagonists for all these functions. As examples, D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg (B9430) is an extremely potent and long-acting antagonist of both B1 and B2 receptors, is stable against endogeneous kininase enzymes, and is active in various in vivo models, including by intragastric administration. Acylation of B9430 with dehydroquinuclidine-2-carboxylic acid (Dhq) gives B9562, a highly selective B2 antagonist. In contrast, Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic (B9858) is a highly potent and selective B1 antagonist. The dimer of B9430 linked at the amino terminus with suberimide is a potent selectively cytotoxic agent for SCLC cells. Results with these peptides suggest that a new generation of antiinflammatory and anticancer drugs may be at hand.
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PMID:Potent, long-acting bradykinin antagonists for a wide range of applications. 927 54

The hybrid peptide (CA-ME) derived from cecropin A(1-8) and melittin (1-12) has potent antibacterial and antimalarial activities. Because the N-terminal sequence 1-12 of magainin 2 is similar to melittin(1-12), CA-MA with CA(1-8) and MA(1-12) and their analogues were designed and synthesized. Antitumor activities of these peptides were evaluated using three small cell lung cancer cell lines. Greater antitumor activity was observed when the residues 16, 18 and 19 of the peptide were hydrophobic (Leu or Val), basic (Lys) and basic (Lys), respectively. The IC50 values of the peptides with the residues were 2 to 4 microM. Residue 12 was related to hemolytic activity rather than antitumor activity. Increase in amphipathicity of P4 enhanced hemolytic activity without significant change in antitumor activity. The alpha-helicity of the peptides in a 30 mM sodium dodecyl sulfate solution was more closely correlated to hemolytic activity than antitumor activity.
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PMID:Structure-antitumor and hemolytic activity relationships of synthetic peptides derived from cecropin A-magainin 2 and cecropin A-melittin hybrid peptides. 935 66

The human small cell lung cancer NCI-H69 cell line selected for resistance to etoposide (H69/VP) has been reported previously to sequentially overexpress both the MRP and MDR1 multidrug resistance-conferring genes. In addition, immunocytochemistry of H69/VP cells demonstrated a distinct extranuclear localization of the nuclear enzyme topoisomerase IIalpha, the target of etoposide. Immunoblots showed a decrease in Mr 170,000 topoisomerase IIalpha in nuclear extracts in H69/VP but equal amounts of the enzyme in whole-cell extracts. Topoisomerase II catalytic activities in H69 and H69/VP whole-cell extracts were equal, as were their inhibition by etoposide. Sequencing of the entire H69/VP topoisomerase IIalpha cDNA showed a homozygous 9-nucleotide deletion encompassing nucleotides 4468-76, coding for Lys-Ser-Lys, overlapping two potential bipartite nuclear localization signals. The deletion occurred at the initial nine nucleotides of an exon, suggesting alternative splicing of topoisomerase IIalpha mRNA. Subsequent sequencing of H69/VP genomic DNA revealed a G-->T point mutation in the 3' acceptor splice site consensus sequence, resulting in the use of an alternate splice site. Comparison with previous reports on three drug-resistant cell lines with large truncations/deletions in the COOH-terminal region of topoisomerase IIalpha and extranuclear localization point to a pivotal role for the basic cluster 1490Lys-Ser-Lys1492 in the nuclear import of this enzyme.
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PMID:Loss of amino acids 1490Lys-Ser-Lys1492 in the COOH-terminal region of topoisomerase IIalpha in human small cell lung cancer cells selected for resistance to etoposide results in an extranuclear enzyme localization. 937 50

The effects of camptothecin-somatostatin (CPT-SS) conjugates were investigated on small cell lung cancer (SCLC) cells. CPT was coupled to a SS agonist (SSA), c(Cys-Phe-DTrp-Lys-Thr-Cys)Thr-NH2 using the built in nucleophile assisted-releasing group (L1) N-methyl-aminoethyl-Gly-Dser-Nle-Dtyr-Dser or (L2) aminoethyl-Gly-Dser-Nle-Dtyr-Dser. The resulting CPT-L1-SSA and CPT-L2-SSA inhibited the specific binding of [125I-Tyr11]SS to NCI-H69 cell membranes with IC50 values of 0.2 and 2.1 nM, respectively. [125I]CPT-L1-SSA was internalized by SCLC cells at 37 degrees C but not at 4 degrees C. CPT-L1-SSA and CPT-L2-SSA inhibited in a dose-dependent manner the increase in adenylylcyclase activity caused by 25 microM forskolin. In vitro, 0.3 microM CPT-L1-SSA half-maximally inhibited the clonal growth of SCLC cells and 1 microM CPT-L1-SSA strongly inhibited 3H-thymidine incorporation into DNA and trypan-blue exclusion. These results suggest that CPT conjugated peptides such as CPT-L1-SSA may prove useful for exploring the efficacy of receptor-directed cytotoxicity to inhibit the proliferation of SCLC cells.
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PMID:Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells. 1611 93

Histone proteins are subject to a range of post-transcriptional modifications in living cells. The combinatorial nature of these modifications constitutes the "histone code" that dictates chromatin structure and function during development, growth, differentiation, and homeostasis of cells. Deciphering of the histone code is hampered by the lack of analytical methods for monitoring the combinatorial complexity of reversible multisite modifications of histones, including acetylation and methylation. To address this problem, we used LC-MSMS technology and Virtual Expert Mass Spectrometrist software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys(57) from histone H2B. The dose-response results obtained by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational modifications is a viable approach for functional analysis of candidate drugs, such as HDAC inhibitors.
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PMID:Quantitative proteomic analysis of post-translational modifications of human histones. 1662 69

Bradykinin (BK)-related peptides stimulate two major classes of receptors, B1 and B2. The B1 receptor (B1R) plays an important role in various pathophysiological states including chronic inflammation, pain, hypotension, trauma and proliferation of cancer. Therefore, there is interest in the development of highly potent peptide BK B1R antagonists. We previously developed a highly potent and selective BK B1R receptor antagonist, B9958 (Lys-Lys-[Hyp3, CpG5, d-Tic7, CpG8]des-Arg9-BK) (Hyp, trans-4-hydroxyproline; CpG, alpha-cyclopentylglycine; Tic, tetrahydroisoquinoline-3-carboxylic acid). We now report on new BK B1R antagonist analogs of B9958 with N-terminal basic residues in the d-configuration, or Lys-, Orn- derivatives (NiK, epsilon-nicotinoyllysine; PzO, 3-pyrazinoylornithine) and/or having hindered unusual amino acids at position 5 (Igl, alpha-(2-indanyl)glycine). These changes were designed to prevent enzyme degradation while keeping an acceptable affinity. However, these new analogs do not show higher B1R antagonist activity than B9958, but its N-terminal acylated derivative with a bulky and hydrophobic 2,3,4,5,6-pentafluorocinnamic acid (F5c), B10324, retains a B1R antagonist activity close to that of B9958 and, in addition, has high inhibition in vivo against lung cancer (SCLC, 86 %) and moderate inhibition against prostate cancer (PC3, 43%) xenografts. This class of compounds offers hope for the development of new BK antagonist peptide drugs for lung or prostate cancer.
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PMID:Structural modification of the highly potent peptide bradykinin B1 receptor antagonist B9958. 1818 42


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