Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed the diagnostic value of circulating VEGF as a tumor marker in patients with lung cancer and compared its clinical utility with that of other markers such as carcinoembryonic antigen (CEA) and cytokeratin 19 (CYFRA). One hundred and sixty non-small cell lung cancer patients and 70 healthy volunteers were included in the study. Circulating VEGF was assessed by enzyme-linked immunosorbent assay (ELISA). The serum concentrations of both CEA and CYFRA were measured by means of immunoradiometric assays. The diagnostic value of plasma VEGF (VEGFp) was better than that of CYFRA and similar to that of CEA. When the diagnostic value of VEGFp and CEA for the diagnosis of adenocarcinoma was compared, the two markers proved to have nearly equal discriminatory power. In diagnosing squamous cell carcinoma, VEGFp showed less discrimination than CYFRA. When the diagnostic value of VEGFp was analyzed for stage I adenocarcinoma patients, VEGFp was slightly more discriminatory than CEA. The combination assay of VEGFp and CEA had a sensitivity of 75% and a specificity of 60% at a cutoff of 104.4 pg/mL for VEGFp and 5.2 ng/mL for CEA. The combination of VEGF and CEA was superior to CEA alone in the early diagnosis of adenocarcinoma of the lung.
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PMID:Diagnostic value of plasma vascular endothelial growth factor as a tumor marker in patients with non-small cell lung cancer. 1252 Nov 32

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
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PMID:Pharmacology of imatinib (STI571). 1252 70

Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is involved in cell differentiation, proliferation, and apoptosis, and was recently shown to be regulated by hypoxia. The present immunohistochemical study demonstrates extensive nuclear expression of the protein in 38% of a series of 115 non-small cell lung carcinomas using a polyclonal antibody (Ab) recognizing DEC1 protein. Such expression was directly related to the expression of two hypoxia-regulated proteins, namely the hypoxia-inducible factor (HIF) 1alpha and carbonic anhydrase-9. Although DEC1 was not related to angiogenesis or to the expression of VEGF and thymidine phosphorylase, a direct association with up-regulated bFGF receptors was noted. DEC1 was persistently expressed in the nuclei of normal bronchial and alveolar tissue. It is suggested that loss of DEC1 expression is an early event in the development of lung cancer, while DEC1 gene expression occurs in a subset of tumours and parallels the overexpression of other hypoxia-regulated proteins.
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PMID:DEC1 (STRA13) protein expression relates to hypoxia- inducible factor 1-alpha and carbonic anhydrase-9 overexpression in non-small cell lung cancer. 1275 44

Two receptors, neuropilin 1 (NP1) and neuropilin 2 (NP2), bind class 3 semaphorins, axon guidance molecules including SEMA3F, the gene for which was isolated from a 3p21.3 deletion in lung cancer. In addition, they bind VEGF (vascular endothelial growth factor), enhancing the effects of VEGF binding to KDR/Flk-1. Elevated VEGF levels are associated with the loss and cytoplasmic delocalization of SEMA3F in lung cancer, suggesting competition for their NP1 and NP2 receptors. To determine the timing of these events, we compared by immunohistochemistry VEGF, SEMA3F, NP1 and NP2 expression in 50 preneoplastic lesions and 112 lung tumours. In preneoplastic lesions, VEGF increased from low-grade to high-grade dysplasia (p=0.001) whereas SEMA3F levels remained low. NP1 and NP2 levels increased from dysplasia to microinvasive carcinoma (p=0.0001) and correlated with VEGF expression (p=0.04 and 0.0002, respectively). Non-small cell lung carcinoma overexpressed VEGF and NP1 and NP2 significantly more often than neuroendocrine tumours including small cell lung carcinoma. SEMA3F loss or delocalization correlated with advanced tumour stage. Migrating cells overexpressed VEGF, SEMA3F, NP1 and NP2 with cytoplasmic delocalization of NP1 as demonstrated in an in vitro wound assay. These results demonstrate early alteration of the VEGF/SEMA3F/NP pathway in lung cancer progression.
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PMID:Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines. 1284 30

Lung cancer is the most common visceral malignancy in males, with rapidly increasing incidence in females, and a devastatingly poor prognosis. Transforming growth factor (TGF)-beta has been shown to induce senescence in A549 lung cancer cells, and both TGF-beta and bone morphogenetic protein (BMP) 2 can suppress the transformed phenotype of A549 cells in vitro. We examined the effects of BMP4, another member of the TGF-beta superfamily, on specific oncogenic properties of A549 cancer cells. When A549 cancer cells were treated continuously with 100 ng/ml of BMP4, a senescent phenotype was observed after 2 wk of treatment. The BMP-treated cells appeared larger than untreated cells, grew more slowly, had more senescence-associated beta-galactosidase activity, and had less telomerase activity, as measured by the telomeric repeat amplification protocol assay. Invasion through Engelbreth Holm-Swarm matrix was inhibited in the senescent cell population. Senescent BMP4-treated cells had lower ERK activation, VEGF expression, and Bcl2 expression than wild-type cells, consistent with a less proliferative, less angiogenic phenotype with increased susceptibility to death by apoptosis. BMP4 treatment also resulted in sustained elevation of Smad1. In vivo xenograft studies in the flanks of nude mice confirmed that the BMP-treated cells were significantly less tumorigenic than untreated cells. Direct overexpression of Smad1 using adenoviral constructs resulted in cell death within 5 days. These studies suggest that BMP4 pathway signaling can induce senescence and thus negatively regulate the growth of A549 lung cancer cells.
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PMID:BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. 1295 28

Exposure to second hand smoke (SHS) is believed to cause lung cancer. Pathological angiogenesis is a requisite for tumor growth. Lewis lung cancer cells were injected subcutaneously into mice, which were then exposed to sidestream smoke (SHS) or clean room air and administered vehicle, cerivastatin, or mecamylamine. SHS significantly increased tumor size, weight, capillary density, VEGF and MCP-1 levels, and circulating endothelial progenitor cells (EPC). Cerivastatin (an inhibitor of HMG-coA reductase) or mecamylamine (an inhibitor of nicotinic acetylcholine receptors) suppressed the effect of SHS to increase tumor size and capillary density. Cerivastatin reduced MCP-1 levels, whereas mecamylamine reduced VEGF levels and EPC. These studies reveal that SHS promotes tumor angiogenesis and growth. These effects of SHS are associated with increases in plasma VEGF and MCP-1 levels, and EPC, mediated in part by isoprenylation and nicotinic acetylcholine receptors.
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PMID:Second hand smoke stimulates tumor angiogenesis and growth. 1452 47

Significant advances in the treatment of lung cancers, especially advanced-stage non-small cell lung cancer, have been marginal despite decades of intensive basic research and clinical trial testing. Among the newest class of promising drugs being tested is the angiogenesis inhibitor. The recent success of a randomized phase III trial testing an antivascular endothelial growth factor (VEGF) antibody with chemotherapy for the treatment of metastatic colon cancer has raised hopes that antiangiogenic drugs will have similar benefits for the treatment of lung cancer. Ironically, the sheer number and diversity of such drugs makes selecting the most promising candidates difficult. More detailed and definitive information on the specific factors that induce angiogenesis in types of lung cancer, such as the relative importance of VEGF or other proangiogenic growth factors in non-small cell lung cancer, small cell lung cancer, and mesothelioma angiogenesis, is therefore clearly needed. The nonangiogenic phenotype of some non-small cell lung cancers may render this subset particularly difficult to treat with angiogenesis inhibitors; such tumors, however, may be promising candidates for acute-acting vascular-targeting agents. As with other types of cancer, success with angiogenesis inhibitors will no doubt depend on a number of factors including screening patients' tumors for presence or absence of a particular drug target (eg, bioactive VEGF receptor-2 bound VEGF) when targeting VEGF, selecting the optimal biologic/therapeutic doses of antiangiogenic drugs, monitoring antiangiogenic drug activity in tumors, and determining optimal combinations to use with chemotherapy regimens.
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PMID:Antiangiogenic drugs and current strategies for the treatment of lung cancer. 1498 81

Melanoma differentiation-associated gene-7 (mda-7), recently classified as interleukin-24 (approved gene symbol IL24), is thought to be a tumor suppressor gene based on the loss of its expression in many different types of cancer. Gene therapy by adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to inhibit the growth of several different tumor cell lines, in vitro and in vivo. We previously demonstrated that Ad-mda7 radiosensitized non-small-cell lung cancer (NSCLC) cell lines by enhancing an apoptosis pathway through the activation of JNK and c-Jun. In the present study, we investigated the efficacy of intratumoral administration of Ad-mda7 combined with ionizing radiation for treating A549 xenograft tumors in nude mice. Substantial and long-lasting inhibition of tumor growth was evident following the combined treatment. Histological examination revealed marked reduction of angiogenic factors (bFGF, VEGF) and microvessel density and enhanced apoptosis in the tumors treated with the combination therapy compared to those treated with Ad-mda7 alone or radiation alone. To confirm the radiosensitizing effect of secreted MDA-7 protein, we performed clonogenic survival assays using human umbilical vein endothelial cells (HUVECs), A549 cells, and normal human lung fibroblasts, CCD16 cells, pretreated with the conditioned medium from 293 cells that had been stably transfected with mda-7 or a control vector. The results showed that MDA-7 protein sensitized HUVECs to ionizing radiation but not A549 cells or CCD16 cells. Our results suggest that Ad-mda7 in combination with radiation enhances apoptosis in the tumors and that secreted MDA-7 protein inhibits angiogenesis by sensitizing endothelial cells to ionizing radiation without affecting other normal cells. We conclude that the combination of mda-7 gene therapy and radiotherapy may be a feasible and effective strategy for treatment of NSCLC.
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PMID:Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. 1519 48

Lung cancer is a deadly disease with high mortality and morbidity. Most cases of lung cancer are due to non-small cell carcinoma, with 16% of cases being small cell carcinoma. The biology at a cellular level is of interest at many levels. Knowing cellular pathways helps to further enhance our knowledge of how lung cancer cells survive, proliferate, and metastasize. The receptor tyrosine kinases (RTKs) located at the cellular membrane are becoming of great interest as sites for targeted therapies for lung cancers. This review will discuss the RTKs that are involved in lung cancers and the newer therapies that are being tested. We will specifically discuss receptors such as epidermal growth factor receptor, c-Kit receptor, VEGF receptor, c-Met receptor, insulin growth factor receptor, and Eph receptor. The inhibitors against the specific RTKs are in various preclinical and clinical trials, and this will be detailed.
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PMID:Receptor tyrosine kinases and inhibitors in lung cancer. 1534 2

The primary determinant of outcome in patients with cancer is the development of distant metastasis. Metastasis is a multistep process involving disruption of cell-matrix adhesion, dissolution of the extracellular matrix, angiogenesis, invasion in the blood vessel wall, extravasation and establishment of a secondary growth. Nowadays, a large number of biochemical and cell biological studies have indicated the important role of extacellular matrix adhesion molecules, proteinases and angiogenic factors in the dissemination of cancer. Cell adhesion molecules, such as integrins, E-cadherin, catenins and CD44 appear to have some prognostic significance, especially in gastric, colorectal and lung cancer patients. Since matrix degrading proteinases are involved in cancer spread, they should be good candidates as prognostic factors. The proteinase which has been investigated in greatest detail is uPA in breast cancer. As a marker of cancer, its main value is to aid in selecting the subgroups of node-negative breast cancer patients that are unlikely to benefit from adjuvant chemotherapy. Cathepsin D and metalloproteinases (MMPs) look promising prognostic markers but further work is needed to establish their utility. Intratumoral angiogenesis is a putative prognostic indicator for some types of cancer. High expression of the angiogenic factor VEGF is associated with angiogenesis and an unfavourable survival.
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PMID:Tumor markers in cancer patients. an update of their prognostic significance. Part II. 1536 89


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