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

This study examined the role of marijuana smoking in the pathogenesis of human lung cancer by measuring DNA damage in alveolar macrophages (AM). The alkaline unwinding method was used to determine DNA single-strand breaks in AM lavaged from non-smokers [NS] and smokers of marijuana [MS], tobacco [TS] or cocaine [CS], either alone or in combination. DNA damage was related to superoxide anion (O2-) production by AM stimulated with phorbol myristate acetate (PMA) and to nitric oxide content of smoke using cellular nitrite (NO2-) concentrations. The percentage of double-stranded DNA present after alkaline unwinding was higher in AM of NS (41 +/- 5% [11]) and CS (41 +/- 4% [9]) versus that of MS (31 +/- 4% [8]), TS (35 +/- 3% [11]), MTS (26 +/- 4% [3]), and CTS (27 +/- 5%* [10]), mean +/- SEM [n], * = p < 0.1 vs. NS). PMA stimulated O2- production by AM from NS and CS was lower than that of other smokers, but the differences were not significant. O2- release, however, had an inverse correlation with DNA single-strand breaks (r = -0.38, p = 0.009). Nitrite content of AM from NS and CS was less than that of other smokers' cells (p < 0.1 for TS & CTS vs. NS), but DNA damage had no relationship to NO2- concentration. We conclude that AM recovered from MS, either alone or in combination with tobacco smoking, show a trend towards DNA damage. Studies utilizing a larger population should verify our findings and further define its relationship to enhanced oxidant production by macrophages.
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PMID:Effects of smoking marijuana, tobacco or cocaine alone or in combination on DNA damage in human alveolar macrophages. 777 50

We have tried to identify the cytotoxic effectors in platelet-mediated tumour cell killing, using two tumour cell lines K562 (a chronic myelogenic leukaemic cell line) and LU99A (a lung cancer cell line), which are both sensitive to platelet cytotoxicity. Cyclo-oxygenase inhibitors, acetylsalicylic acid (ASA) and indomethacin, effectively inhibited the platelet-mediated killing of K562 cells, but not that of LU99A cells. In contrast, inhibitors of the nitric oxide (NO) pathway. NG-nitro-1-arginine (L-NA), haemoglobin and methylene blue, reduced the cytotoxic activity of platelets against LU99A, but not against K562. Synthetic analogues of platelet cyclo-oxygenase products thromboxane A2/ prostaglandin H2(TXA2/PGH2) exerted cytotoxicity against K562 cells but not against LU99A cells. Electron microscopic study showed that TXA2/PGH2 analogues induced bleb formation and disruption of the plasma membrane of K562 cells. K562 cells enhanced the production of TXA2 by platelets, as inferred from the accumulation of thromboxane B2 (TXB2), a spontaneous hydrolysis product of TXA2. LU99A cells had no such effects. These results indicate that platelets kill these two tumour cell lines through different mechanisms. In K562, the cyclooxygenase products TXA2/PGH2 possibly play a significant role but in LU99A the NO pathway seems to be involved.
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PMID:Two mechanisms for platelet-mediated killing of tumour cells: one cyclo-oxygenase dependent and the other nitric oxide dependent. 891 Nov 54

Cigarette smoking is a major cause of human cancer at a variety of sites, although its carcinogenic mechanisms remains unestablished. Cigarette smoke can be divided into two phases, gas phase and particulate matter (tar). Both phases contain high concentrations of oxidants and free radicals, especially nitric oxide (NO) and nitrogen oxides in the gas phase and quinone/hydroquinone complex in the tar. We have found that incubation of pBR322 plasmid DNA with aqueous extracts of cigarette tar and a NO-releasing compound (diethylamine NONOate) caused synergistic induction of DNA single-strand breakage, whereas either cigarette tar alone or NO alone induced much less strand breakage. This synergistic effect of cigarette tar and NO on DNA strand breakage was prevented by high concentrations of superoxide dismutase, carboxy-PTIO (an NO-trapping agent) or N-acetylcysteine, whereas hydroxyl radical scavengers such as dimethylsulfoxide, ethanol and D-mannitol did not show inhibitory effects. Possible mechanisms for this synergistic effect mediated by cigarette tar and NO are proposed, including involvement of peroxynitrite, which is a strong oxidant and nitrating agent formed rapidly by the reaction between NO and O2.-. NO is present in the gas phase of smoke and may be formed by a constitutive or inducible NO synthase in the lung, whereas O2.- is generated by auto-oxidation of polyhydroxyaromatic compounds such as catechol and 1,4-hydroquinone present in cigarette tar. Thus, potent reactive species including peroxynitrite formed by the interaction between cigarette tar and NO may play an important role in smoking-related diseases including lung cancer.
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PMID:Synergistic induction of DNA strand breakage by cigarette tar and nitric oxide. 923 Feb 80

Understanding carcinogenesis is critical for development of rational approaches to cancer prevention. This paper uses N-nitrosamine carcinogenesis as an example. N-Nitrosamines are a large group of potent carcinogens. Approximately 300 different N-nitrosamines are carcinogenic. At least 30 animal species are responsive to their effects. There is little doubt that humans exposed to sufficient amounts of N-nitrosamines would also be susceptible to their carcinogenic effects. Human exposure to preformed N-nitrosamines occurs through the diet, in certain occupational settings, and through the use of tobacco products, cosmetics, pharmaceutical products, and agricultural chemicals. Diminishing human exposure to these carcinogens is one approach to prevention of cancer, and this has been accomplished in many instances, although exposure to N-nitrosamines in tobacco products is still unacceptably high. Human exposure to N-nitrosamines also occurs by nitrosation of amines in the body, via their acid or bacterial catalyzed reaction with nitrite, or by reaction with products of nitric oxide generated during inflammation or infection. A second approach toward prevention of N-nitrosamine carcinogenesis is inhibition of this endogenous N-nitrosamine formation. Substantial reductions have been achieved with ascorbic acid and other nitrite scavengers. N-Nitrosamines undergo a simple cytochrome P450-mediated metabolic activation step, which is critical for their carcinogenicity. The third approach involves the use of chemopreventive agents that block this step, or other steps in the carcinogenic process. A large number of potent chemopreventive agents against nitrosamine carcinogenesis have been identified. Chemoprevention of lung cancer induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is discussed as an example of this approach.
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PMID:Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis. 934 87

Nitric oxide synthases (NOS) exist in human tumor cell lines and solid tumor tissues, and it has been suggested that NO may play important roles in growth, progression or metastasis of tumors. We investigated the activity and distribution of NOS in a series of human cancer and normal lung tissues. Seventy-two primary lung cancer samples (44 cases of adenocarcinoma, 18 of squamous cell carcinoma, 4 of large cell carcinoma, 2 of small cell carcinoma, 2 of adenosquamous carcinoma, and 2 of carcinoids) and corresponding normal lung samples were obtained from surgically treated patients. In normal lung tissues, little NOS activity was observed with no correlation between the patient's age and NOS activity. The total NOS activities in lung adenocarcinoma samples were significantly higher than those in other types of lung cancers of normal lung samples (P < 0.05). Analysis by tumor grade of the adenocarcinoma samples revealed no significant difference of NOS activity between grades. TNM classification showed that, although T stage did not correlate with NOS activity, cancer tissues from patients with N2 disease tended to have lower activity than those from patients with NO or N1 disease. Immunohistochemical studies revealed that the intensity of NOS immunoreactivity correlated with NOS activity. These results suggest that NO may play an important role in the metabolism and behavior of lung cancers, especially adenocarcinoma.
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PMID:Nitric oxide synthase activity in human lung cancer. 947 37

Vascular endothelial growth factor (VEGF) expression and mutations of cancer-related genes increase with cancer progression. This correlation suggests the hypothesis that oncogenes and tumour suppressors regulate VEGF, and a significant correlation between p53 alteration and increased VEGF expression in human lung cancer was reported recently. To further examine this hypothesis, we analysed VEGF protein expression and mutations in p53 and K-ras in 27 non-small-cell lung cancers (NSCLC): 16 squamous cell, six adenocarcinomas, one large cell, two carcinoids and two undifferentiated tumours. VEGF was expressed in 50% of the squamous cell carcinomas (SCC) and carcinoids but none of the others. p53 mutations occurred in 14 tumours (52%), and K-ras mutations were found in two adenocarcinomas and one SCC; there was no correlation between the mutations and VEGF expression. As nitric oxide also regulates angiogenesis, we examined NOS expression in NSCLC. The Ca2+-dependent NOS activity, which indicates NOS1 and NOS3 expression, was significantly reduced in lung carcinomas compared with adjacent non-tumour tissue (P < 0.004). Although the Ca2+-independent NOS activity, which indicates NOS2 expression, was low or undetectable in non-tumour tissues and most carcinomas, significant activity occurred in three SCC. In summary, our data do not show a direct regulation of VEGF by p53 in NSCLC. Finally, we did not find the up-regulation of NOS isoforms during NSCLC progression that has been suggested for gynaecological and breast cancers.
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PMID:Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. 968 99

Monocyte-macrophage series have an important role in host surveillance against cancer. The cytotoxic/cytostatic activity of macrophages is, to a great extent, attributed to the up-regulation of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). Here, in 28 patients with primary lung cancer and 20 control subjects, we measured the concentration of exhaled NO and nitrite in epithelial lining fluid (ELF) using a chemiluminescence NO analyser, and studied NOS expression in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescence intensity (FI) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 +/- 15.2 FI, normal side 232.4 +/- 18.6 FI; n = 28) compared with that in control subjects (27.3 +/- 3.2 FI; n = 20, P< 0.001). The level of exhaled NO from cancer patients (16.9 +/- 0.9 p.p.b.; n = 28) was significantly higher than that in the control group (6.0 +/- 0.5 p.p.b.; n = 20, P < 0.001). The level of nitrite was also significantly higher in ELF from cancer patients (tumour side 271.1 +/- 28.9 nM and normal side 257.4 +/- 19.6 nM vs control subjects 32.9 +/- 4.1 nM; P< 0.001). The intensity of iNOS expression in AM was correlated with the level of exhaled NO (rs = 0.73, n = 76, P< 0.001) and the nitrite released in ELF (rs = 0.56, n = 76, P< 0.001). The nitrite generation of cultured AM from patients with lung cancer was significantly enhanced compared with that of control subjects after culture for 24 h (tumour side 5.75 +/- 0.69 and normal side 5.68 +/- 0.58 microM per 106 cells vs control group 38.3 +/- 3.6 nM per 106 cells; P< 0.001). The distribution of iNOS was identified in AM, tumour-associated macrophages, endothelium, chondrocytes, airway epithelium of both lungs and malignant cells (adenocarcinoma and alveolar cell carcinoma) of cancer patients. cNOS was labelled in alveolar macrophages, endothelial cells and nerve elements from lung tissue. Our results indicate that, in patients with primary lung cancer, the production of NO from alveolar macrophages was increased as a result of the up-regulation of iNOS activity. The increased NO production was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory processes of the host.
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PMID:Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. 971 40

The relationship and in situ interactions between interleukin 2 (IL-2)-regulated mediators remain unclear, particularly in lung cancer model. The purpose of the present study was to determine in vitro effect of IL-2 on the secretory activity of bronchoalveolar leukocytes from 11 patients with previously untreated small cell lung cancer (SCLC) and 9 patients with non-small cell lung cancer (NSCLC). Control group (n = 6) comprised patients who underwent diagnostic investigations and were free of any clinical or radiographic evidence of lung diseases. IL-2-induced secretion of mediators was compared with that following stimulation with lipopolisaccharide (LPS; 5 micrograms/ml) or Newcastle disease virus (NDV; 640 HU/ml). Obtained from bronchoalveolar lavages (BAL) cells were cultured for 24-48 h in the presence or absence of inducers. The levels of cytokines were determined in BAL cell supernatants by bioassays. Nitric oxide (NO) was estimated by colorimetric method in Griess reaction. Compared with normal controls, the spontaneous secretion of the above mediators excluding IFN-gamma in BAL cultures from NSCLC group was elevated by up to 20-30-fold and further increase was observed after stimulation with LPS. However, very low secretion of cytokines and NO was found in BAL leukocyte cultures activated by IL-2. In contrast, the cells obtained from SCLC group produced little detectable levels of TNF-alpha (median 12.0, range 3-45 U/ml), IFN-gamma (median 3, range 3-12 U/ml) and IL-6 (median 15, range 6-45 U/ml) in response to LPS and interferons, mainly IFN-alpha; (median 3, range 3-12 U/ml) in response to NDV. Although, upon IL-2-stimulation was observed only noteworthy production of IL-6 (median 405, range 45-1215 U/ml). IL-2-induced secretion of IL-6 was accompanied by up to 5-fold augmented secretion of NO in comparison with NSCLC group and healthy controls. These observations suggest that BAL cells from patients with lung cancers express a selective secretory activity and that IL-2 is an important regulatory factor of secondary production of IL-6 and NO. Utilization of IL-2 in therapeutic strategy in SCLC can lead to alterations in synthesis/release of biologically active IL-6 and NO that may contribute to the clinical settings.
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PMID:Exogenous interleukin 2 regulates interleukin 6 and nitric oxide but not interferon gamma and tumor necrosis factor alpha production in bronchoalveolar leukocytes from patients with small cell lung cancer. 988 16

Molecular mechanisms of interplay between reactive oxygen (superoxide, hydroxyl radical, H2O2 etc.) and nitrogen (nitric oxide - NO, ONOO-, NO2-, NO3- etc.) forms are proposed to be of key importance for cell and tumor biology. Considering NO as a signal molecule we have studied the impact of NO release on processes of generation of H2O2 in different experimental systems including pleural effusions (PE) of lung cancer patients, human polymorphonuclear leukocytes (PMNs), and rat thymocytes. It was found that PE of lung cancer patients contain a high level of [NO2-+NO3-], i.e. 43.4 25.6 microM (n=15), and PE cells could effectively generate H2O2 in response to lectins from Viscum album (VAA), Phaseolus vulgaris (PHA), and Pisum sativum (PSA) as well as to menadione. A positive correlation between the [NO2-+NO3-] concentration and menadione-induced H2O2 generation (r=0.1964) was found, whereas the [NO2-+NO3-] concentration and lectin-induced H2O2 generation (PHA, r=-0.4099; PSA, r=-0.3949; VAA, r=-0.3225) were negatively correlated. Notably, an increase of H2O2 generation by PE cells was determined in the range of 20-35 microM [NO2-+NO3-]. When PMNs and rat thymocytes were treated with a donor of NO (sodium nitroprusside), the release of H2O2 in response to lectins or menadione was decreased in a dose-dependent manner. The end products of NO biochemistry, assayed as KNO2 and KNO3, were not able to affect significantly the H2O2 generation processes. In conclusion, the data indicate that the potential for triggered H2O2-generation of cells is modulated markedly by the presence of NO or derived reaction compounds. This relation may play an important role in the pathogenesis of PE malignancies with potential relevance for therapeutic strategies.
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PMID:NO-dependent regulation of lectin- and menadione-induced H2O2 production by cells from pleural effusions of lung cancer patients and by immune cells. 1008 31

CD40-CD40 ligand (CD40L) interaction was originally defined as important molecules for the development of humoral immunity. Thereafter, some investigations have focused on its essential roles for the induction of cell-mediated immunity in host defenses. Here we investigated the antitumor activity of murine alveolar macrophages through CD40-CD40L interaction. The CD40L gene was transfected into murine lung cancer cells (3LLSA), and CD40L-expressing clones (3LLSA-CD40L) were established. Stimulation of CD40 molecules on the surface of alveolar macrophages with 3LLSA-CD40L cells induced the production of nitric oxide, tumor necrosis factor-alpha, and interleukin-12 and the tumoricidal activity of alveolar macrophages in the presence of interferon-gamma, which increased the surface expression of CD40 molecules on alveolar macrophages. These findings were not observed when alveolar macrophages were obtained from CD40-deficient mice. On the other hand, interleukin-6 production by alveolar macrophages did not depend on CD40-CD40L interaction. We also established a murine melanoma cell line expressing CD40L (B16 4A5-CD40L) that could induce tumoricidal activity of alveolar macrophages. Furthermore, when spleen cells were cocultivated with 3LLSA-CD40L cells, specific cytotoxic T lymphocytes for wild-type 3LLSA cells could be induced. These results suggest that CD40L gene transfer into tumor cells may induce antitumor immunity in a tumor-bearing host and may offer a new strategy for cancer gene therapy.
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PMID:Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand interaction. 1040 30


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