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)

Lung cancer is the most frequently occurring cancer in the world and causes more deaths in the United States than does colon, breast, and prostate cancer combined. Despite advances in treatment modalities including radiation, surgery, and chemotherapy, the overall survival in lung cancer remains low. The cytokine tumor necrosis factor alpha (TNFalpha) has been shown to regulate both apoptotic and antiapoptotic pathways. Activation of the transcription factor NF-kappaB appears to be the critical determinant of the antiapoptotic response to TNFalpha exposure in epithelial cells. A549 human lung carcinoma cells were infected with adenoviral constructs carrying dominant negative mutants of Rac1 and IKK or constitutively active mutant of Rac1, upstream effectors in TNF-mediated NF-kappaB activation. Cell death, apoptosis, and NF-kappaB activation were subsequently measured in response to TNFalpha exposure. Although TNFalpha alone had no cytotoxic effect, the expression of the dominant negative mutant of IKKbeta (Ad.IKKbetaKA) resulted in apoptotic cell death following TNFalpha exposure. Similarly, dominant negative mutant to Rac1 (Ad.N17Rac1) further sensitized A549 cells to IKKbetaKA-mediated TNFalpha-induced cell death. Conversely, a dominant active form of Rac1 (Ad.V12Rac1) ameliorated the cell death response to concurrent IKKbeta dominant negative mutant infection and TNFalpha exposure. These results suggest that concurrent inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-induced apoptosis.
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PMID:Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-mediated apoptosis. 1177 80

Substrates for CYP2C9 include fluoxetine, phenytoin, warfarin, losartam and numerous nonsteroidal anti-inflammatory drugs. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino-acid residues 144 Arg/Cys and 359 Ile/Leu of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, the frequency of this allele is, however, rather low. Consistently with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. The polymorphic enzyme CYP2C9 takes part in the metabolism of alkylating agents and polycyclic aromatic hydrocarbons like benzo(a)pyrene, a carcinogen present in tobacco smoke. Although the impact of impaired enzyme activity in metabolism of carcinogens and procarcinogens has not been fully defined, an association of CYP2C9 variant alleles to DNA adduct levels in lung tissues as well as to lung cancer risk have been reported. In this study 64 healthy subjects (44M/22F) were analysed for CYP2C9 genotype with PCR-RFLP and for serum carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CA 19-9, CA 15-3, ferritin, IL-6, IL-8 concentrations by chemiluminescence or electrochemiluminescence methods. CYP2C9*1 was found to be the most prevalent allele and CYP2C9*1/CYP2C9*1 was the most frequent genotype represented in 64% of the population in southeastern Anatolia (Gaziantep). Although slight differences in serum tumour marker and cytokine concentrations were observed for CYP2C9 genotypes the differences were statistically insignificant (P > 0.05). This could be due to the complexity of the role of CYP2C9 in benzo(a)pyrene metabolism as well as from other contributing factors like interindividual variability of diverse enzymes participating in the same metabolic pathway, unequal expression of the variant alleles and differences in exposure to carcinogens. However, determination of CYP2C9 phenotypes in a larger group of subjects might clarify these slight differences.
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PMID:Cytochrome P4502C9 genotype in Southeast Anatolia and possible relation with some serum tumour markers and cytokines. 1183 86

The cytokines expressed in tumor microenvironments are thought to be important mediators of both the host immune response and tumor survival. The source of these cytokines includes tumor cells, infiltrating leukocytes, fibroblasts, and other stromal elements. We previously reported that tumor-infiltrating lymphocytes (TIL) from human non-small cell lung cancer (NSCLC) express predominantly type 1 cytokines, which are known to enhance cell-mediated immunity. The purpose of this study is to assess the cytokine mRNA expression of human NSCLC primary cell lines and the capacity of the tumor-associated cytokines to modulate the development of TIL cytolytic activity against the autologous tumor. Cytokine mRNA expression was determined by RT-PCR and the capacity of TIL to kill autologous lung tumor cells was measured by the chromium-51 (51Cr) release assay. All NSCLC primary cell lines expressed mRNA for IL-4, IL-6, and transforming growth factor-beta1 (TGFbeta1), whereas IL-10 was expressed in only 1/7 cell lines. When added to TIL cultures stimulated with anti-CD3+IL-2, IL-4 and IL-10 enhanced and TGF-beta1 suppressed the development of TIL cytolytic activity against autologous tumor cells. The effects of IL-6 were inconsistent and for the group, were not statistically significant. These results demonstrate that human NSCLC cells express cytokines with the capacity to regulate the in situ anti-tumor immune response. However, the effects of tumor-derived cytokines varied qualitatively and quantitatively suggesting the balance between specific type 2 cytokines or TGF-beta1 within tumor microenvironments may influence prognosis or response to immunotherapy.
Lung Cancer 2002 Apr
PMID:Modulation of tumor-infiltrating lymphocyte cytolytic activity against human non-small cell lung cancer. 1189 Oct 29

A human/severe combined immunodeficient mouse chimeric model was used to demonstrate that peripheral blood leukocytes (PBLs) from a patient with lung cancer completely suppress the growth of an autologous tumor in a PBL dose-dependent fashion repeatedly and over a 4-year period. Suppression of the patient's tumor required CD4+ T cells, CD56+ natural killer cells, and CD14+ monocytes/macrophages, but was completely independent of CD8+ T cells. The CD4+ effector cells promoted tumor killing indirectly because direct tumor recognition and killing are precluded by the absence of MHC class I and II molecules on the tumor cells. Tumor suppression was found to require both human interleukin-12 (IL-12) and IFN-gamma, which were produced and released by the patient's monocytes and T cells, respectively. These results establish that human CD4+ T cells present in the peripheral blood of a patient with lung cancer are able to orchestrate cytokine-dependent killing of an autologous MHC-negative tumor indirectly and without codependence on CD8+ T cells. We conclude that human tumor suppression is achieved in vivo even in the absence of MHC molecules on tumor cells. This tumor suppression is mediated indirectly by cytokines produced by the patient's PBLs that ultimately initiate tumor killing via several, presently incompletely defined mechanisms.
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PMID:Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice. 1198 Jun 57

Leptin is an anorexia inductor peptide produced by adipocytes and related to fat mass. Leptin is also produced by fat under proinflammatory cytokine action. Our objective is to study serum leptin levels in relation to nutritional status and acute phase response in advanced-stage non-small cell lung cancer.Seventy-six patients newly diagnosed of non surgical non-small cell lung cancer before chemotherapy treatment and 30 healthy controls were included. BMI, serum leptin and cholesterol levels and lymphocyte count were decreased in lung cancer patients. Cytokine IL-6, TNF-alpha, sTNF-RII, sIL-2R, IL-12, IL-10 and IFN-gamma, and other acute phase reactants as alpha1 antitrypsin, ferritin, CRP and platelets were all raised in patients, whereas the IL-2 was decreased. We found a direct relationship between leptin and other indicators of the status of nutrition, especially total fat mass. We also found a close relationship between the status of nutrition and the performance status (Karnofsky index). However, serum leptin and nutritional status were inversely correlated with acute phase proteins and proinflammatory cytokines, suggesting a stress-type malnutrition. Although serum leptin levels, nutritional status and Karnofsky index are related to survival, at multivariate analysis they all were displaced by the acute phase reaction markers. These results suggest that cancer anorexia and cachexia are not due to a dysregulation of leptin production. Circulating leptin concentrations are not elevated in weight-losing cancer patients and are inversely related to the intensity of the inflammatory response. In advanced lung cancer patients serum leptin concentrations only depend on the total amount of fat.
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PMID:Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the status of nutrition? 1220 Jan 9

IL-6 is a multifunctional cytokine involved in differentiation and proliferation of immune cells. Moreover, it has diverse effects on the proliferation of tumor cells in vivo and in vitro. Although stimulating cell growth of multiple myeloma cells, it inhibits the proliferation of B16 melanoma cells and lung cancer cells. B9.55 cells, B-cell lymphoma, are IL-6-dependent cells, definitely requiring exogenous IL-6 for growth. When the cDNA for IL-6 was transfected into B9.55 cells, they began growing in an autocrine pattern without exogenous IL-6. To investigate the effects of IL-6 on B9.55 lymphoma in vivo, IL-6-transfected B9.55 cells (B9.G7) or neotransfected B9.55 cells (B9.vec) were injected subcutaneously into syngeneic mice. Initially, B9.G7 outgrew B9.vec, but after 3 weeks, B9.G7 grew slower than B9.vec. In addition, 5 micro g of recombinant human IL-6 was injected daily into the tumor site. Reduced tumor sizes of IL-6-treated rats, similar to those observed in mice which received B9.G7, indicated that IL-6 itself is the mediator of tumor regression. When B9.G7 cells were injected into the irradiated normal mice, tumor regression was released compared with the untreated normal control, suggesting that radiosensitive host components were involved in the regression of B9.G7 cell growth. However, the tumor regression of B9.G7 cells was not released in SCID mice. Histologically, B9.G7 tumor demonstrated severe necrosis and apoptotic cells with infiltration of host inflammatory cells. Above data indicate that IL-6 functions as an autocrine growth factor for B9.G7 cells in vitro, but behaves as an autocrine inhibiting factor in vivo. These contrasting effects of IL-6 on tumor cells in vitro and in vivo will be facilitative in understanding the interaction of cytokines and host immune systems.
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PMID:IL-6 Undergoes Transition from in vitro Autocrine Growth Factor toin vivo Growth Inhibitor of B Lymphoma Cells. 1238 81

The addition of 2500 i.u./ml interferon alpha (IFNalpha) for 48 h induced apoptosis, and caused an approx. 4-fold increase in the activity and expression of tissue transglutaminase (tTG), in human lung cancer H1355 cells. However, the increase in mRNA levels for tTG was just 1.6-fold. On the basis of these data, we investigated whether tTG levels may be regulated through regulation of its degradation via ubiquitination. It was found that 2500 i.u./ml IFNalpha induced a time-dependent decrease in tTG ubiquitination. On the other hand, addition of the proteasome inhibitor lactacystin led to accumulation of the ubiquitinated form of the enzyme and to a consequent increase in its expression. Treatment of the cells with the two agents combined antagonized the accumulation of the ubiquitinated isoforms of tTG induced by lactacystin and caused a potentiation of tTG expression. Moreover, the tTG inducer retinoic acid was also able to cause increased expression and ubiquitination of tTG in H1355 cells. The addition of monodansylcadaverine (a tTG inhibitor) to IFNalpha-treated H1355 cells completely antagonized growth inhibition and apoptosis induced by the cytokine. In conclusion, we demonstrate for the first time that tTG is ubiquitinated and degraded by a proteasome-dependent pathway. Moreover, IFNalpha can, at least in part, induce apoptosis through the modulation of this pathway.
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PMID:Ubiquitination of tissue transglutaminase is modulated by interferon alpha in human lung cancer cells. 1240 Nov 32

Cancer development and ageing are complex sciences. From the study on the process of rodent carcinogenesis, we identified tumor necrosis factor-alpha (TNF-alpha) as an important mediator of cancer development. This paper presents three clinical examples of TNF-alpha up-regulation: by cord factors of Mycobacterium tuberculosis, such as trehalose 6-monomycolate, as an activator of protein kinase C and by a cord factor like fraction of Microsporum canis obtained in the air inside houses in Thailand, both of which are risk factors in human lung cancer development, and by Helicobacter pylori gene product, H. pylori membrane protein 1 (HP-MP1) in relation to human stomach cancer. The second part of this paper deals with down-regulation of TNF-alpha by a wide variety of cancer preventive agents. Among the various agents, (-)-epigallocatechin gallate (EGCG) and green tea polyphenols inhibited TNF-alpha gene expression in the cells induced by tumor promoter, mediated through inhibition of NF-kappaB activation. Studying growth inhibition of human cancer cell lines by morphine, we found that morphine and the new morphine derivatives KT-90 and KT-87 have anticancer activity mediated through induction of apoptosis, in addition to analgesic action. We conclude that environmental and endogenous factors induce NF-kappaB activation mediated through expression of inflammatory cytokine genes, such as TNF-alpha, and that the expression pattern of the genes operates similarly in the aging process.
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PMID:Involvement of TNF-alpha changes in human cancer development, prevention and palliative care. 1247 Sep 3

The use of appropriate antigenic peptides for the most common human major histocompatibility complex (MHC) alleles is required for the amplification of the autologous cytotoxic compartment and the development of cytotoxic T cell-mediated immunity. The human A2 allele of the MHC plays an important role for the identification of peptide-specific cytotoxic T cells (CTL) against tumor and viral epitopes. Computer-based prediction algorithms, which are available on the Internet, have already proved to be applicable for the identification of novel CTL epitopes. Using the bioinformatics approach, the authors have identified the novel influenza matrix protein-derived and HLA-A3-restricted 9-mer peptide RLEDVFAGK capable of inducing peptide specific CTL reactivity. Peripheral blood mononuclear cells (PBMC) from healthy individuals and patients with lung cancer were pulsed with this peptide and with the well-characterized HLA-A2-restricted influenza A virus matrix peptide GILGFVFTL. Using quantitative PCR (TaqMan; Applied Biosystems, Foster City, CA, U.S.A), reactivity for both peptides was determined by measuring the change in type 1 cytokine (IFN-gamma) expression upon in vitro stimulation. Peptide-specific reactivity matched well with the subsequently determined MHC-class I alleles of the tested individuals. Results from this study indicate that the use of bioinformatics and the PCR-based screening system for the monitoring of T cell reactivity may allow for the identification of novel CTL epitopes.
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PMID:Immune reactivity against a novel HLA-A3-restricted influenza virus peptide identified by predictive algorithms and interferon-gamma quantitative PCR. 1251 28

Interferons (IFNs) are a family of cytokine mediators that are critically involved in alerting the cellular immune system to viral infections of host cells. There are three major classes of IFNs, as follows: IFN-alpha; IFN-beta; and IFN-gamma. IFNs are being investigated and applied in various respiratory disorders, including interstitial lung diseases, lung cancer, malignant mesothelioma, malignant pleural effusions, and respiratory infections. Recent promising preliminary results concerning patients with idiopathic pulmonary fibrosis who have been treated with IFN-gamma1b should prompt the performance of further confirmatory well-designed multicenter trials. IFN-gamma is emerging as an important cytokine for use in the treatment of patients with infectious diseases, including multidrug-resistant pulmonary TB. A better understanding of IFN biology, indications, side effect profiles, and toxicity management will aid in optimizing its use in the treatment of patients. The purpose of this article is, therefore, to review the current clinical use of IFNs in the treatment of patients with respiratory diseases.
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PMID:Interferons and their application in the diseases of the lung. 1466 34


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