Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new polyelectrolyte was synthesized and evaluated for antitumor activity. The product is a derivative of ethylene/maleic anhydride copolymer of low molecular weight (Mn approximately equal to 1100). The anhydride groups were first converted to the half-amide, half-ammonium salt by reaction with ammonia. A percentage (14-25 wt %) of these groups was further converted to the imide by heating. The product, carboxyimamidate (Carbethimer, N-137) inhibited the growth of a number of solid tumors in vivo. Sensitive tumor models included Lewis lung carcinoma, Madison 109 lung carcinoma, M5076 ovarian tumor, colon carcinoma 26, B16 melanoma, and P815 mastocytoma. Activity was dose related between nontoxic dose levels of 300 and 2000 mg/kg ip.
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PMID:Carboxyimamidate, a low-molecular-weight polyelectrolyte with antitumor properties and low toxicity. 713 85

Gallium nitrate (NSC-15200), a group IIIa metal salt, was evaluated in a phase I-II clinical trial, In phase I trial, exploring bolus administration of the drug at 3-week intervals, dose-limiting renal toxicity was observed at doses exceeding 700 mg/m2. Hematological toxicity was minimal. Ototoxicity was observed in one patient. A phase-II trial was initiated evaluating the drug at 700 mg/m2 given at 2- and 3-week intervals. Antitumor responses were observed in one patient with soft-tissuesarcoma and in two patients with small cell carcinoma of the lung. In two of these responders, pretreatment 67Ga scan was positive. Further clinical trials with the drug appear indicated, utilizing the every 2 week schedule. Pretreatment hydration combined with osmotic diuresis may ameliorate potential nephrotoxicity.
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PMID:Phase I-II clinical trial of gallium nitrate (NSC-15200). 742 36

Defensins, antimicrobial and cytotoxic peptides of neutrophils, bind to and are inactivated by blood proteins. We identified defensin interactions with alpha 1-proteinase inhibitor (alpha 1-PI), alpha 1-antichymotrypsin (alpha 1-ACT), alpha 2-antiplasmin (alpha 2-AP), and antithrombin III (AT III) and examined defensin binding to alpha 1-PI and alpha 1-ACT in more detail. Defensin interactions with either alpha 1-PI or alpha 1-ACT were not affected by iodoacetamide or high salt concentration. Preincubation of alpha 1-ACT or alpha 1-PI with increasing concentrations of defensin resulted in a progressive decrease of antiprotease activity of both inhibitors against cathepsin G and antiprotease activity of alpha 1-PI against human neutrophil elastase. At higher concentrations, defensin also ablated the inhibitory effect of normal human serum on cathepsin G and human neutrophil elastase. Both alpha 1-PI and alpha 1-ACT inhibited defensin cytotoxicity toward the human lung carcinoma cell line A549, whereas the elastase inhibitor antileukoprotease did not. Complex interactions between serpins and defensin may have a role in regulating inflammatory processes.
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PMID:Human neutrophil defensin and serpins form complexes and inactivate each other. 787 2

Fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF) play a pivotal role in the multistep pathway of tumor progression, metastasis, and angiogenesis. We have identified a porphyrin analogue, 5,10,15,20-tetrakis(methyl-4-pyridyl)-21H,23H-porphine-tetra -p-tosylate salt (TMPP), as a potent inhibitor of FGF2 and VEGF receptor binding and activation. TMPP demonstrated potent inhibition of binding of soluble FGF receptor 1 (FGFR1) to FGF2 immobilized on heparin at submicromolar concentrations. TMPP inhibits binding of radiolabeled FGF2 to FGFR in a cell-free system as well as to cells genetically engineered to express FGFR1. Furthermore, TMPP also inhibits the binding of VEGF to its tyrosine kinase receptor in a dose-dependent manner. In an in vitro angiogenic assay measuring the extent of endothelial cell growth, tube formation, and sprouting, TMPP dramatically reduced the extent of the FGF2-induced endothelial cell outgrowth and differentiation. In a Lewis lung carcinoma model, mice receiving TMPP showed a marked inhibition of both primary tumor progression and lung metastases development, with nearly total inhibition of the metastatic phenotype upon alternate daily injections of TMPP at 25 microg/g of body mass. Finally, novel meso-pyridylium-substituted, nonsymmetric porphyrins, as well as a novel corrole-based derivative, with >50-fold increase in activity in vitro, had a significantly improved efficacy in blocking tumor progression and metastasis in vivo.
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PMID:Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis. 1085 Apr 45

Calu-3 cells, a human lung carcinoma cell line with properties like serous cells of the upper airway, were used to develop an in vitro model for airway antibacterial activity. Calu-3 cell monolayers were cultured on permeable supports at an air-liquid interface. Apical surface fluid (ASF) was collected by washing; antibacterial activity was assayed by incubating ASF washings with bacteria for 18 h and counting surviving colony-forming units. ASF washings killed Escherichia coli and Pseudomonas aeruginosa. Antibacterial activity was salt sensitive and dependent on protein concentration. After washing, approximately 30 h were required before antibacterial activity recovered to its initial level. After culturing with topical corticosteroids (budesonide, triamcinolone, or beclomethasone, 0.1 microg/ml for 48 h), ASF antibacterial activity was 4- to 10-fold greater than the ASF from control monolayers. The increase in antibacterial activity was dose-dependent. The beta(2)-agonists salbutamol and terbutaline (100 microg/ml for 48 h) decreased ASF antibacterial activity by 5- to 8-fold. The nonsteroidal anti-inflammatory agents ibuprofen and cromolyn sodium had no effect. Our results are most consistent with agonist-dependent changes in the composition of ASF antibacterial proteins. We conclude that Calu-3 cells synthesize and secrete antibacterial proteins and that clinical agents can alter these functions.
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PMID:Antibacterial activity of apical surface fluid from the human airway cell line Calu-3: pharmacologic alteration by corticosteroids and beta(2)-agonists. 1150 29

Patients with small-cell lung carcinoma (SCLC) rarely present with pleural effusions. Based on morphology alone, recognition of SCLC in effusion cytology may be challenging because of the resemblance of neoplastic cells to lymphocytes. Immunocytochemistry may be helpful in its diagnosis. The objective of this study was to review the morphology and evaluate the use of immunocytochemistry in diagnosing SCLC in pleural fluids. Patients with SCLC who presented with pleural effusions were identified during a 6-yr period. The cytology and medical records were reviewed. Formalin-fixed, paraffin-embedded cell blocks of fluid specimens were immunostained with neuroendocrine markers (chromogranin A and synatophysin), cytokeratin 20 (CK20), and thyroid transcription factor-1 (TTF-1). The latter is a nuclear transcription protein that is expressed in normal respiratory epithelium and also in more than 90% of SCLCs. Of the 256 patients diagnosed with SCLC during the study period, 8 (2.7%) patients (3 females and 4 males, age range from 56-85 yr) also developed pleural effusions. One patient had 2 fluid specimens during the course of their disease, giving a total of 9 specimens. Four specimens had a positive cytologic diagnosis of SCLC, and 2 were initially diagnosed as suspicious for SCLC. The remaining 3 specimens were negative for SCLS. The specimens with a positive or suspicious diagnosis showed single and aggregates of small to medium-sized single cells with a high nuclear:cytoplasmic (N:C) ratio, round to angulated nuclei, and salt-and-pepper chromatin. Nuclear molding was also noted. Five out of 6 (83%) specimens with a positive or suspicious diagnosis of SCLC were positive for both chromogranin A and TTF-1. Synaptophysin was positive in 3 of 6 (50%) positive or suspicious cases. None of the cases were positive for CK20. All cases with a negative cytologic diagnosis were negative for chromogranin A, synatophysin, CK20, and TTF-1. In conclusion, patients with SCLC rarely present with pleural effusions. The cytology of SCLC is characteristic. The use of immunocytochemistry, particularly with antibodies to chromogranin A, TTF-1, and CK 20, aids in the differential diagnosis.
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PMID:Malignant pleural effusions due to small-cell lung carcinoma: a cytologic and immunocytochemical study. 1174 31

Glycosaminoglycans (GAGs) are complex polysaccharides that participate in the regulation of physiological processes through the interactions with a wide variety of proteins. Acharan sulfate (AS), isolated from the giant African snail Achatina fulica, primarily consists of the repeating disaccharide structure alpha-D-N-acetylglucosaminyl (1-->4) 2-sulfoiduronic acid. Exogenous AS was injected subcutaneously near the tumor tissue in C57BL/6 mice that had been implanted with Lewis lung carcinoma cells (LLCs). The location of AS in the tumor was assessed by staining of sectioned tissues with alcian blue and periodic acid-Schiff (PAS) reagent. In vitro assays indicated binding of cells to 50 microg/ml AS (or heparin) after a 5-h incubation. Immunofluorescence assays, using anti-AS antibody, detected AS at the cell surface. The outer-surface of LLCs were next biotinylated to identify the AS-binding proteins. Biotinylated cells were lysed, and the lysates were fractionated on the AS affinity column using a stepwise salt gradient (0, 0.1, 0.3, 0.5, 0.7, 1.0, and 2.0 M). The fractions were analyzed by SDS-PAGE with silver staining and western blotting. We focused on the proteins with high affinity for AS (eluting at 1 M NaCl) and detected only two bands by western blotting. ESI Q-TOF MS analysis of one of these bands, molecular weight approximately 110 kDa, showed it to be nucleolin. A phosphorylated form of nucleolin on the surface of cells acts as a cell surface receptor for a variety of ligands, including growth factors (i.e., basic fibroblast growth factor) and chemokines (i.e., midkine). These results show that nucleolin is one of several AS-binding proteins and suggest that AS might demonstrate its tumor growth inhibitory activity by binding the nucleolin receptor protein on the surface of cancer cells.
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PMID:Nucleolin: acharan sulfate-binding protein on the surface of cancer cells. 1532 57

CI-1033 (N-[4-[N-(3-chloro-4-fluorophenyl)amino-7-[3-(4-morpholynyl)propoxy]quinazolin-6-yl]acrylamide, PD 0183805-mesylate salt) was identified as a potent, selective inhibitor of erbB family tyrosine kinases, which are overexpressed in a number of solid tumors and have been shown to be involved in tumor progression. Because objective response of clinical patients to erbB-targeted therapies like CI-1033 has been observed only in a subset of cancer patients that exhibit the intended molecular targets, much emphasis has been placed on the identification of biomarkers of antitumor efficacy. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) were considered as potential biomarkers for CI-1033 due to ease of detection in patient plasma and showed roles in angiogenesis and cancer progression and positive regulation by the erbB receptor family. In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated. Oral administration of CI-1033 to tumor-bearing mice at efficacious doses resulted in markedly decreased levels of VEGF and/or IL-8 plasma levels and tumor mRNA levels relative to vehicle-treated control mice in xenograft models that exhibited evaluable levels of these markers. In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models. These studies indicate that plasma VEGF and IL-8 may have use as biomarkers of antitumor efficacy for epidermal growth factor receptor/erbB-targeted therapies such as CI-1033 and suggest that further clinical study of these markers in cancer patients are warranted.
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PMID:Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor. 1595 51

Several metals are carcinogenic but little is known about the mechanisms by which they cause cancer. A pathway that may contribute to metal ion induced carcinogenesis is by hypoxia signaling, which involves a disruption of cellular iron homeostasis by competition with iron transporters or iron-regulated enzymes. To examine the involvement of iron in the hypoxia signaling activity of these metal ions we investigated HIF-1alpha protein stabilization, IRP-1 activity, and ferritin protein levels in human lung carcinoma A459 cells exposed to various agents in serum- and iron-free salt-glucose medium (SGM) or in normal complete medium. We also studied the effects of excess exogenous iron on these responses induced by nickel ion exposure. Our results show the following: (1) SGM enhanced metals-induced HIF-1alpha stabilization and IRP-1 activation (e.g., nickel and cobalt ions). (2) If SGM was reconstituted with a slight excess level (25 microM of FeSO(4)) of iron, this enhancing ability was significantly decreased. (3) The effect of a high level of exogenous iron (500 microM of FeSO(4)) on metal-induced hypoxia and iron metabolism was highly dependent on the order of addition. If treatment with the Fe and metal ions was simultaneous (co-treatment), the effects of nickel ion exposure were overwhelmed, since the added Fe reversed HIF-1alpha stabilization, decreased IRP-1 activity, and increased ferritin level. Pre-treatment with iron was not able to reverse the responses caused by nickel ion exposure. These results imply that it is important to consider the available iron concentration and suitable exposure design when studying metal-induced hypoxia or metal-induced disruption of Fe homeostasis.
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PMID:Effect of metal ions on HIF-1alpha and Fe homeostasis in human A549 cells. 1687 34

The development of anticancer metal-based drugs was attempted by reacting dodecyl amine with selenious acid to produce a quaternary ammonium salt which was then converted to copper and cobalt cationic complexes via complexing the first compounds with copper (II) or cobalt (II) ions. The surface properties of these surfactants were investigated. The surface properties studied included critical micelle concentration (CMC), maximum surface excess (Gamma max ), and minimum surface area (A min ). Free energy of micellization (Delta G degree mic ) and adsorption (Delta G degree ads ) were calculated. Antitumor activity was tested by using Ehrlich ascites carcinoma (EAC) as a model system of mice cell tumor. The compounds were also tested in vitro on five human monolayer tumor cell lines: MCF 7 (breast carcinoma), HEPG 2 (liver carcinoma), U 251 (brain tumor), HCT 116 (colon carcinoma), and H 460 (lung carcinoma). FTIR spectra, elemental analysis, and H 1 NMR spectra were performed to insure the purity of the prepared compounds.
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PMID:Surface and antitumor activity of some novel metal-based cationic surfactants. 1827 Mar 94


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