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

AdmATF is a recombinant adenovirus encoding a secreted version of the amino-terminal fragment (ATF) of murine urokinase (uPA). This defective adenovirus was used in three murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad cell invasion inhibitor that antagonizes uPA binding to its cell surface receptor (uPAR). A single intratumoral injection of AdmATF into pre-established MDA-MB-231 human breast xenografts grown in athymic mice, or into pre-established C57/BL6 syngeneic Lewis lung carcinoma resulted in a specific arrest of tumor growth. Neovascularization within and at the vicinity of the injection site was also suppressed, suggesting that AdmATF inhibited primary tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites: (1) lung dissemination of Lewis lung carcinoma cells was significantly reduced following intratumoral injection at the primary site; and (2) systemic administration of AdmATF inhibited subsequent liver metastasis in a LS174T human colon carcinoma xenograft model. These data outline the potential of using a recombinant adenovirus directing the secretion of an antagonist of cell-associated uPA for cancer gene therapy.
 ...
PMID:Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. 1032 34

Although fibrinolysis has been implicated in the progression and metastasis of lung cancer, no detailed study has been carried out on components measured in samples from both plasma and tumour. This study thus provides the first comprehensive data obtained from 166 patients diagnosed with non-small cell lung carcinoma. Plasma samples were obtained at diagnosis and tumour samples during surgical resection. Appropriate control samples were obtained from normal subjects and patients with chronic obstructive airways disease (plasma) and from organ donors (normal lung tissue). Assays were performed on plasma and tissue extracts for tissue plasminogen activator, urokinase-like activator and plasminogen activator inhibitor (activity and antigen in all cases), together with plasmin-antiplasmin complex, soluble fibrin, D-dimer and thrombin-antithrombin complex. Levels of D-dimer, thrombin-antithrombin complex and plasmin-antiplasmin complex were all significantly higher in plasma from patients, whereas urokinase-like activator activity was reduced. Only two parameters were significantly altered in both the core and periphery of tumour tissue: levels of D-dimer were increased and tissue-type plasminogen activator activity was reduced. Interestingly, significant differences in levels of other fibrinolytic parameters were detected in the core and periphery of tumours. Significant activation of fibrinolysis was indicated in patients, although the origin of this could not be related consistently to changes in levels of plasminogen activator and inhibitor.
 ...
PMID:Alterations to the fibrinolytic enzyme system in patients with non-small cell lung carcinoma. 1045 17

The urokinase-type plasminogen activator (uPA) interacts with its receptor (uPAR) to promote proteolysis as well as cell proliferation and migration. These functions contribute to the pathogenesis of neoplastic growth and invasiveness. Expression of uPAR in tumor extracts also inversely correlates with prognosis in many forms of cancer. In this study, we sought to determine if differences in uPAR expression were distinguishable between cultured human lung carcinoma and malignant mesothelioma subtypes. We also sought to determine if, as in malignant mesothelioma cells, uPAR expression is regulated at the posttranscriptional level in cultured malignant lung carcinoma cells. Using 125I-uPA binding and ligand blotting techniques, uPAR was expressed by phenotypically diverse lung carcinoma cell lines, including the H460, H157 and H1395 non-small cell lines and the H146 small cell lung carcinoma line. Increased uPAR expression was also detected in spindle-shaped (M33K) and epithelioid (M9K and MS-1) malignant mesothelioma cells. Selected mediators, including TGF-beta, TNF-alpha, LPS and PMA, uniformly enhanced uPAR expression in each of the tumor cell lines. Steady state uPAR mRNA expression was determined by RNase protection assay and correlated directly with the changes in cell surface uPAR expression. By gel mobility shift and UV-cross linking assays, a uPAR mRNA binding protein (uPAR mRNABp) implicated in the posttranscriptional control of message stability, was identified in each of the cell lines. Expression of uPAR and its message in cultured lung carcinoma and malignant mesothelioma cells is similarly influenced by effectors present in the tumor microenvironment. Regulation of the uPAR message occurs at the posttranscriptional level in cultured small and non-small cell lung carcinoma cells as well as spindle-shaped and fibrous malignant mesothelioma cell lines. Posttranscriptional regulation of uPAR in all these cells involves the interaction of the uPAR mRNABp with uPAR mRNA, which promotes uPAR mRNA destabilization.
 ...
PMID:Posttranscriptional regulation of urokinase receptor gene expression in human lung carcinoma and mesothelioma cells in vitro. 1054 67

Chromium(VI) regulation of gene expression has been attributed to the generation of reactive chromium and oxygen species, DNA damage, and alterations in mRNA stability. However, the effects of Cr(VI) on signal transduction leading to gene expression are not resolved. Therefore, this study investigated the effects of Cr(VI) on basal and tumor necrosis factor-alpha (TNF-alpha)-induced transcriptional competence of nuclear factor-kappaB (NF-kappaB) in A549 human lung carcinoma cells. Pretreatment of A549 cells with nontoxic levels of Cr(VI) inhibited TNF-alpha-stimulated expression of the endogenous gene for interleukin-8 and of an NF-kappaB-driven luciferase gene construct, but not expression of urokinase, a gene with a more complex promoter. Chromium did not inhibit TNF-alpha-stimulated IkappaBalpha degradation or translocation of NF-kappaB-binding proteins to the nucleus. However, Cr(VI) pretreatments prevented TNF-alpha-stimulated interactions between the p65 subunit of NF-kappaB and the transcriptional cofactor cAMP-responsive element-binding protein-binding protein (CBP). This inhibition was not the result of an effect of chromium on the protein kinase A catalytic activity required for p65/CBP interactions. In contrast, Cr(VI) caused concentration-dependent increases in c-Jun/CBP interactions. These data indicate that nontoxic levels of hexavalent chromium selectively inhibit NF-kappaB transcriptional competence by inhibiting interactions with coactivators of transcription rather than DNA binding.
 ...
PMID:Chromium(VI) inhibits the transcriptional activity of nuclear factor-kappaB by decreasing the interaction of p65 with cAMP-responsive element-binding protein-binding protein. 1059 7

The anti-tumor and anti-metastatic effects of 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid (TAC-101) were investigated using our established lung cancer model. Orthotopic implantation of Lewis lung carcinoma (LLC) cells into the lung parenchyma produced a solitary tumor nodule in the lung followed by mediastinal lymph node metastasis. Daily oral administration of TAC-101 at doses ranging from 4 to 16 mg/kg resulted in a significant inhibition of lymphatic metastasis (inhibition rate=57 to 76%), while only the dose of 16 mg/kg significantly inhibited tumor growth at the implanted sites (inhibition rate=46%). Combined treatment with cis-diamminedichloroplatinum (CDDP) and TAC-101 (8 mg/kg, p.o., daily) enhanced the anti-tumor effect of CDDP (7 mg/kg, i.v., bolus) against both the growth of implanted tumor and lymphatic metastasis. In addition, this combined treatment significantly prolonged the survival time of LLC tumor-bearing mice as compared to treatment with each agent alone. The anti-activating protein-1 (AP-1) activity of TAC-101 caused inhibition of LLC cell invasion through the repression of expression of urokinase-type plasminogen activator and its receptor. The anti-invasive activity of TAC-101 may be involved in its in vivo anti-metastatic activity. These findings suggest that TAC-101 is a novel anti-cancer agent that may improve the therapeutic modalities for lung cancer patients with metastatic disease.
 ...
PMID:TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) inhibits spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. 1062 38

Plasminogen activator inhibitor-1 (PAI-1), the major circulating inhibitor of urokinase [urokinase-type plasminogen activator (uPA)], has been linked to the pathogenesis of lung cancer. PAI-1 belongs to the serpin family of inhibitors and inhibits both free urokinase (uPA) and receptor-bound urokinase (uPA receptor). Although PAI-1 has been related to a poor prognosis in lung carcinoma, mechanisms that regulate its expression in human lung cancer cells are not well understood. We used cultured human small cell and non-small cell lung carcinoma cell lines as model systems to elucidate the regulatory mechanisms that control expression of PAI-1. Levels of PAI-1 protein were significantly increased in selected lung carcinoma cells compared with those in normal small-airway epithelial cells. Corresponding steady-state levels of PAI-1 mRNA were similarly increased in these cells. The half-life of PAI-1 mRNA was prolonged in these lung carcinoma cell lines after transcriptional or translational blockade. We identified a 60-kDa protein that binds the 3'-untranslated region of PAI-1, and complex formation of this binding protein with PAI-1 mRNA reciprocally correlates with mRNA stability. The findings demonstrate that expression of PAI-1 is regulated at the posttranscriptional level in small cell- and non-small cell-derived human lung carcinoma cell lines. Altered regulation of PAI-1 at the posttranscriptional level may contribute to relative overexpression by malignant lung epithelial cells. A newly identified regulatory protein that binds to the 3'-untranslated region of PAI-1 mRNA appears to be involved in the posttranscriptional regulation of PAI-1 gene expression by human lung carcinoma cells in vitro.
 ...
PMID:Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung carcinoma cells in vitro. 1064 2

We sought to determine if urokinase expression is regulated at the post-transcriptional level in cultured lung epithelial cells. We also sought to determine if differences in urokinase expression by cultured human lung carcinoma and non-malignant lung epithelial subtypes were attributable to post-transcriptional regulatory mechanisms. Urokinase was expressed by phenotypically diverse lung carcinoma cell lines as well as non-malignant small airway epithelial cells and bronchial epithelial cells. Using gel mobility shift and UV cross-linking assays, we identified a 30-kDa urokinase mRNA-binding protein that selectively bound to a 66-nucleotide protein-binding fragment of urokinase mRNA. The urokinase mRNA-binding protein is found in the cytosolic but not nuclear extracts of non-malignant lung epithelial cells; whereas, it is found in the nuclear but not cytosolic extracts of selected malignant carcinoma-derived cells that express relatively large amounts of urokinase. Chimeric beta-globin/urokinase cDNA containing the urokinase mRNA-binding protein binding sequence destabilized otherwise stable beta-globin mRNA. Our results demonstrate that urokinase gene expression in lung epithelial and lung carcinoma-derived cells is regulated at the post-transcriptional level. The mechanism involves an interaction between a 66-nucleotide sequence of the urokinase mRNA 3'-untranslated region with a newly recognized urokinase mRNA-binding protein to regulate urokinase mRNA stability.
 ...
PMID:Post-transcriptional regulation of urokinase mRNA. Identification of a novel urokinase mRNA-binding protein in human lung epithelial cells in vitro. 1078 98

We examined the effect of berberine, a major component with anti-fungal properties contained in Coptidis Rhizoma and Phellodendri Cortex, on the lymph node metastasis of murine lung cancer. Oral administration of berberine for 14 days significantly inhibited the spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma (LLC) into the lung parenchyma in a dose-dependent manner, but did not affect the tumor growth at the implantation site of the lung. Combined treatment with berberine and an anti-cancer drug, CPT-11, resulted in a marked inhibition of tumor growth at the implantation site and of lymphatic metastasis, as compared with either treatment alone. Anti-activator protein-1 (anti-AP-1) transcriptional activity of non-cytotoxic concentrations of berberine caused the inhibition of the invasiveness of LLC cells through the repression of expression of urokinase-type plasminogen activator (u-PA).
 ...
PMID:Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. 1124 16

Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.
 ...
PMID:Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer. 1168 58

Using the intrabronchial orthotopic propagation method, we evaluated the biological characteristics of human adenocarcinoma cell lines in vivo and examined the expressions of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and their related proteins. Nine human lung adenocarcinoma cell lines, including A549, NCI-H23, NCI-H322, NCI-H358, Calu-3, PC-14, LC-2/ad, RERF-LC-KJ and PL16T, were injected into the peripheral bronchi of mice using this method. The mice were sacrificed at 4 and 8 weeks after tumor cell propagation and the lungs and other organs were observed macroscopically and histologically. We classified the adenocarcinoma cell lines, according to their intrapulmonary tumorigenicity, into the following three groups: (A) those that showed a high incidence of intrapulmonary implantation (>50%) (A549 and NCI-H358). A549 showed mediastinal lymph node metastasis and pleural dissemination; (B) those that showed a low incidence of intrapulmonary implantation (PC-14, NCI-H322, NCI-H23, Calu-3, and LC-2/ad); (C) those that showed no tumorigenicity in the lung (RERF-LC-KJ and PL16T). In order to characterize the biological differences between each cell line, we investigated the expressions of MMP-2 and MMP-9 and their related molecules by northern blot analysis. The expressions of MMP-2 and MMP-9 and their activators (membrane-type 1-MMP and urokinase-type plasminogen activator) were thought to be associated with the growth, invasion and metastasis of the human lung adenocarcinoma cell lines examined.
Lung Cancer 2002 Jun
PMID:Intrabronchial orthotopic propagation of human lung adenocarcinoma--characterizations of tumorigenicity, invasion and metastasis. 1200 37


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