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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To facilitate the detection of invading tumor cells in a three dimensional coculture assay in vitro, the reporter gene Escherichia coli beta-galactosidase (lacZ), was transfected into a human large-cell lung carcinoma cell line GaL23. Multicellular spheroids initiated from the transfected cell line, GaL23LZ, were confronted with fragments of human bronchial tissue differing in their surface composition. While an intact surface epithelium was found to obstruct both adhesion and invasion of tumor cells, an exposed basal lamina augmented adhesion, migration and invasion of tumor cells into the normal tissue. Tumor cells, migrating on the surface of the bronchial fragments, were found to migrate between the epithelial cells and the basal lamina. Fibroblast covered stromal fragments, derived from resected non-small cell lung cancers, were found to be more edible to the invading tumor cells than subepithelial stromal fragments from normal bronchi. The lacZ transfection made it possible to quantitatively analyze the invasive process. While the transfection neither changed the invasive ability of the tumor cells in vitro or in vivo nor their growth pattern in monolayers, three dimensional growth represented by spheroid morphology and clonogenicity in soft agar was significantly changed. This model offers an in vitro system to study qualitative and quantitative aspects of tumor-host relationships in a complex microenvironment which has several similarities to the in vivo situation.
Lung Cancer 1998 Jul
PMID:Invasiveness by lacZ transfected non-small-cell lung cancer cells into human bronchial tissues in vitro. 979 49

Development of methods for gene transfer into specific cell types or tissues is important for experimental research as well as clinical therapeutical approaches. We report here the cloning and characterization of the envelope (env) gene and the U3 region of a retrovirus from an infected human Small Cell Lung Cancer (SCLC) cell line. The replication of this murine retrovirus is also fully supported by other lung cancer cell lines of different histological origin. We present evidence that a long terminal repeat (LTR)-beta-galactosidase (beta-Gal) reporter construct performed as well as an analogous cytomegalovirus (CMV) promoter beta-Gal construct in the human lung epithelial cell line A549 and in the human larynx carcinoma cell line HEp2.
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PMID:Envelope and long terminal repeat sequences of an infectious murine leukemia virus from a human SCLC cell line: implications for gene transfer. 985 89

The use of tissue- or tumor-selective promoters in targeted gene therapy for cancer depends on strong and selective activity. Hexokinase type II (HK II) catalyzes the first committed step of glycolysis and is overexpressed in tumors, where it is no longer responsive to normal physiological inhibitors, e.g., glucagon. We show, in a reporter gene assay, activation of HK II in non-small cell lung carcinomas NCI-H661 and NCI-H460 at 61 and 40%, respectively, relative to the activation observed with a constitutive promoter, while it was only 0.9% in different preparations of primary normal human bronchial epithelial cells (NHBECs). Similar results were observed in a variety of normal and tumor cells. Moreover, treatment of the transfectants with glucagon did not inhibit promoter activation in the transformed H661 cells, while endogenous HK II in NHBECs is suppressed by glucagon. H460 and H661 cells infected with a recombinant adenovirus carrying an HK II/LacZ expression cassette, AdHexLacZ, demonstrated beta-galactosidase activity that correlated with the level of HK II promoter activation in these cells. Under similar conditions, no enzyme activity was observed in NHBECs. Cells were then infected with AdHexTk and treated with GCV. Our results demonstrate selectivity in toxicity, with a 10- to 100-fold increase in IC50 between lung cancer cell lines H661 and H460, respectively, and NHBECs. There was also a 100-fold increase in IC50 in NHMECs relative to breast carcinoma cell line MCF-7. In HepG2 cells, an IC50 of 1 microg/ml was observed, comparable to that of other tumor cell lines. This represents a novel use of the hexokinase type II as a selective promoter in cancer gene therapy.
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PMID:Hexokinase type II: a novel tumor-specific promoter for gene-targeted therapy differentially expressed and regulated in human cancer cells. 1002 41

We have developed RNA molecules capable of effecting spliceosome-mediated RNA trans-splicing reactions with a target messenger RNA precursor (pre-mRNA). Targeted trans-splicing was demonstrated in a HeLa nuclear extract, cultured human cells, and H1299 human lung cancer tumors in athymic mice. Trans-splicing between a cancer-associated pre-mRNA encoding the beta-subunit of human chorionic gonadotropin gene 6 and pre-trans-splicing molecule (PTM) RNA was accurate both in vitro and in vivo. Comparison of targeted versus nontargeted trans-splicing revealed a moderate level of specificity, which was improved by the addition of an internal inverted repeat encompassing the PTM splice site. Competition between cis- and trans-splicing demonstrated that cis-splicing can be inhibited by trans-splicing. RNA repair in a splicing model of a nonfunctional lacZ transcript was effected in cells by a PTM, which restored significant beta-galactosidase activity. These observations suggest that spliceosome-mediated RNA trans-splicing may represent a general approach for reprogramming the sequence of targeted transcripts, providing a novel approach to gene therapy.
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PMID:Spliceosome-mediated RNA trans-splicing as a tool for gene therapy. 1009 82

Current paradigms in cancer therapy suggest that activation of nuclear factor-kappaB (NF-kappaB) by a variety of stimuli, including some cytoreductive agents, may inhibit apoptosis. Thus, inhibiting NF-kappaB activation may sensitize cells to anticancer therapy, thereby providing a more effective treatment for certain cancers. E-1-deleted adenoviral (Ad) vectors encoding a "superrepressor" form of the NF-kappaB inhibitor IkappaBalpha (AdIkappaBalphaSR) or beta-galactosidase (AdLacZ) were tested alone and in combination with tumor necrosis factor-alpha (TNF-alpha) in lung cancer cells for sensitization of the cells to death. Following transduction with AdIkappaBalphaSR, lung cancer cells expressed IkappaBalphaSR in a dose-dependent manner. Probing nuclear extracts of lung cancer cells with NF-kappaB-sequence-specific oligonucleotides indicated that there was a minimal amount of NF-kappaB in the nucleus at baseline and an expected and dramatic increase in nuclear NF-kappaB following exposure of cells to TNF-alpha. Control E-1-deleted AdLacZ did not promote NF-kappaB activation. Importantly, AdIkappaBalphaSR-mediated gene transfer resulted in the complete block of nuclear translocation of NF-kappaB by specific binding of its p65/relA component with transgenic IkappaBalphaSR. At the cellular level, transduction with AdIkappaBalphaSR resulted in increased cytotoxicity in lung cancer cells as opposed to transduction with equivalent doses of AdLacZ. In addition, whereas the parental cells were resistant to TNF-alpha-mediated cytotoxicity, IkappaBalphaSR-transduced cells could be sensitized to TNF-alpha. Consequently, AdIkappaBalphaSR transduction followed by exposure to TNF-alpha uniformly resulted in the death of non-small-cell lung cancer cells. These data suggest that novel approaches incorporating IkappaBalpha gene therapy may have a role in the treatment of lung cancer.
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PMID:IkappaBalpha gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them to tumor necrosis factor-alpha-mediated cell death. 1042 7

Esophagitis is a major toxicity of radiation therapy for nonsmall-cell lung cancer. Intraesophageal injection of manganese superoxide dismutase (MnSOD) plasmid/liposome complexes (1 mg of the pRK5-MnSOD plasmid containing the human MnSOD transgene in a 0.15 ml volume of lipofectin) before irradiation was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fraction 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formation in squamous lining cells, separation of the squamous layer from the underlying muscle layer, ulceration at 7 days, and dehydration and death by 30 days. MnSOD plasmid/liposome complex-injected mice showed transcription of the human MnSOD transgene message in esophageal squamous lining cells by nested reverse transcriptase-polymerase chain reaction (RT-PCR) increased MnSOD biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survival (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial beta-galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopathology and decreased survival. Mice receiving intraesophageal MnSOD plasmid/liposomes followed 8 h later by human equivalent doses of Taxol (1.4 mg/kg) and carboplatin (2.5 mg/kg), then 15 h later 3,300 cGy irradiation, showed increased survival, compared with irradiated control or LacZ plasmid/liposome groups. Thus, overexpression of the human MnSOD transgene in the esophagus can prevent irradiation-induced esophagitis in the mouse model.
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PMID:Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. 1049 61

New modalities of treatment for small-cell lung cancer (SCLC) are needed, because the majority of patients continue to die of disseminated disease despite an initial response to conventional chemotherapy. Abnormal surface expression of the neural-cell adhesion molecule (NCAM) has been noted to be highly associated with SCLC. We examined the ability and efficiency of a streptavidin-Protein A (ST-PA) fusion protein complexed with an anti-NCAM monoclonal antibody (Mab) to transfer biotinylated beta-galactosidase into human SCLC cell lines NCI-H69, NCI-H526, and NCI-H446. When the surface molecule NCAM was targeted with this system, more than 99% of the targeted cells internalized and exhibited beta-galactosidase activity. In addition, we evaluated cytotoxic activity against SCLC lines NCI-H69 and NCI-H526 by efficient delivery of biotinylated glucose oxidase using the same ST-PA/anti-NCAM Mab complex. Cytotoxicity of the transduced cells (SCLC) was 10-fold and 100-fold greater, respectively, than the glucose oxidase control. This system could be widely applied for specific therapy of cancer cells by targeting unique surface molecules (antigens) using the corresponding Mab/ST-PA complex to transfer a variety of effector molecules; e.g., immunotoxic compounds, into target cells with a high degree of efficiency and specificity.
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PMID:Specific cell targeting for delivery of toxins into small-cell lung cancer using a streptavidin fusion protein complex. 1094 28

Replication-defective adenoviruses are arousing growing interest as both gene therapy and vaccine vectors. In a phase I clinical trial designed to evaluate the feasibility and tolerance of recombinant adenovirus (rAd)mediated gene transfer, we previously demonstrated that a single intratumoral injection of 10(9) PFU of rAd encoding the beta-galactosidase protein (Ad-beta-Gal) induced strong short-term (1-3 months) humoral, helper (Th1 type) and cytotoxic T cell responses specific for the transgene product in patients with advanced lung cancer. The purpose of the present study was to evaluate the persistence of long-lasting immunity to the transgene protein and in parallel, to assess patient immunocompetence revealed by responses to recall antigens (tetanus toxoid, purified protein derivative), viral pathogens (Epstein-Barr virus, influenza virus), and allogeneic antigens in mixed lymphocytic reactions. The beta-Gal-specific proliferative response declined rapidly in patients with progressive disease, as did responses to the other antigens. In contrast, a long-lasting proliferative response to beta-gal was maintained in an immunocompetent patient in complete remission 2 years after an injection of 108 PFU of Ad-beta-Gal. Anti-beta-Gal humoral (IgG and IgA) responses persisted notably, as did responses to TT and poliomyelytic antigens. While T cell effector cytotoxic responses specific for the viral peptides plummeted, the frequency of anti-beta-Gal CTL precursors remained particularly high, thus attesting to major immunization. Despite the impact of both advanced disease and chemotherapy on immunocompetence, we show the long-term persistence of immunity to the transgene protein vectorized by rAd.
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PMID:Longitudinal follow-up of cellular and humoral immunity induced by recombinant adenovirus-mediated gene therapy in cancer patients. 1098 63

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

In the course of malignant growth processes in patients with lung cancer, a decrease of natural cytotoxic activity of peripheral blood lymphocytes was observed. This process was accompanied by changes of activities of two lysosomal enzymes, arylsulfatase and acid phosphatase, suggesting participation of these enzymes in manifestation of effector functions of lymphocytes in cancer patients. The level of activity of granular enzyme, beta-glucuronidase, remained unchanged at all stages of disease. A study of natural killer activity of C3HA mice splenocytes after inoculation of transplantable hepatoma 22-a cells revealed a relative stability of the level of their cytotoxicity, and of the activities of lysosomal enzymes--arylsulfatase, acid phosphatase, alpha-mannosidase, acid lipase, N-acetyl-beta-D-glucosidase, and beta-galactosidase, beginning from the 3rd day after hepatoma implantation.
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PMID:[The influence of tumor growth on natural cytotoxicity and activity of some lysosomal enzymes of human effector cells and the C3HA mouse splenocytes]. 1559 12


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