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

The aim of the present experiments was to test the possible involvement of nitric oxide (NO) in cytokine-induced enhancement of tumor cell (TC) adhesion to endothelial cells (ECs). Exposure of EA hyb 926 cells to TNF (500 U/ml) plus IFN (100 U/ml) for 24 h significantly enhanced their adhesivity for the 51Cr-labeled GLC1 (small cell lung carcinoma) TCs. Conversely, exposure of TCs to cytokines did not result in an increased adhesion of these cells to ECs. TC-stimulated adhesion to EA hyb 926 was abrogated by the glucocorticoid dexamethasone (Dex, 10(-7) M), the NO synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) and NG-monomethyl-L-arginine (L-NMMA, 10(-5) M) and the protein synthesis inhibitor cycloheximide (Cex, 10(-6) M). Furthermore, GLC1-stimulated adhesion to EA hyb 926 was reversed following removal of L-arginine from the medium or pretreatment with the guanylate cyclase inhibitor methylene blue. TC-stimulated adhesion was also prevented when TCs were pretreated with the monoclonal antibody CD15 directed against the endothelial-leukocyte adhesion molecule (ELAM-1) ligand or following exposure of ECs to anti-ELAM-1 monoclonal antibody. Although suppressing TC-stimulated adhesion, L-NMMA failed to modify significantly cytokine-induced ELAM-1 expression in EA hyb 926. These results (a) provide evidence for the NO-inducible pathway contributing to cytokine-induced enhancement of tumor cell adhesion to the vascular endothelium and (b) demonstrate the involvement of the ELAM-1/CD15 adhesion system in tumor cell-stimulated adhesion to ECs.
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PMID:Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. 128 56

The injection of B16F10 melanoma cells with recombinant human tumor necrosis factor alpha (TNF-alpha) into the tail vein of C57BL/6 mice resulted in 2- to 25-fold more metastatic foci in the lungs than the injection of tumor cells alone. Clearly, TNF-alpha significantly enhanced experimental tumor metastasis. Furthermore, it enhanced the metastasis of Lewis lung carcinoma cells. In contrast, a mutein of TNF-alpha, designated as F4236, having the cell-adhesive sequence (Tyr-Ile-Gly-Ser-Arg) at the N-terminus of the TNF molecule did not enhance metastasis, but rather exhibited similar antitumor activity to wild-type TNF-alpha in fibrosarcoma-bearing mice.
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PMID:A YIGSR-containing novel mutein without the detrimental effect of human TNF-alpha of enhancing experimental pulmonary metastasis. 161 34

We have previously characterized more than 20 proteins induced by the immunoregulatory lymphokine IFN-gamma in human fibroblasts by their m.w. and isoelectric points determined in two-dimensional gels. Some of these proteins are induced uniquely by IFN-gamma, whereas others are also induced by IFN-alpha, TNF, or IL-1. Recent technologic advances have allowed us to begin to rapidly identify proteins induced by IFN-gamma and other cytokines by sequencing the induced proteins from blots of preparative two-dimensional gels of total cell lysates. In this study, we show that the approximately 21 kDa, isoelectric point greater than 7 protein induced by IFN-gamma is manganese superoxide dismutase (Mn-SOD), a mitochondrial protective enzyme encoded by a nuclear gene. Mn-SOD is induced by IFN-gamma and also by TNF in all four human cell lines examined: HS153 fibroblasts, ACHN renal carcinoma, A549 lung carcinoma, and A375 melanoma. Induction of Mn-SOD mRNA is a primary, rapid, and dose-dependent response to IFN-gamma. In ACHN renal carcinoma cells, Mn-SOD mRNA and protein are induced synergistically by IFN-gamma in combination with either TNF or IL-1, and the induced protein is enzymatically active. IFN-gamma and TNF together induce Mn-SOD mRNA by more than 100-fold relative to its level in untreated ACHN cells. The induction of Mn-SOD by IFN-gamma and its synergistic induction by IFN-gamma in combination with TNF and IL-1 should protect healthy cells from the toxicity of O2- during an immune response, and may provide a mechanism for selective killing of infected cells.
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PMID:Manganese superoxide dismutase is induced by IFN-gamma in multiple cell types. Synergistic induction by IFN-gamma and tumor necrosis factor or IL-1. 190

Eight species of novel recombinant tumor necrosis factor-S (rTNF-SAM group) were constructed in which N-terminal amino acid sequences were based on that of TNF-S from THP-1 cells with higher basicity than conventional rTNF-alpha. Two of this rTNF-SAM group, denoted as rTNF-SAM1 and rTNF-SAM2, showed more cytocidal activity on A549 lung carcinoma cells and G401 Wilm's tumor cells than did rTNF-alpha. In addition to these cell lines, rTNF-SAM1 revealed strong cytocidal activity on T24 bladder carcinoma cells, which are resistant to rTNF-alpha. Moreover, possible cachectin activity of rTNF-SAM2 seemed to be lower than that of conventional rTNF-alpha, suggesting that rTNF-SAM2 has less side effects. Actually, toxicity as expressed by LD50 value of rTNF-SAM2 as well as others of the rTNF-SAM group was significantly lower than that of conventional rTNF-alpha. Thus, newly constructed rTNF-SAM1 and rTNF-SAM2 should be more promising antitumor reagents for clinical use, since they were shown to be superior to conventional rTNF-alpha both in antitumor effect and in less side effects.
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PMID:Biological activities of novel recombinant tumor necrosis factor having N-terminal amino acid sequences derived from cytotoxic factors produced by THP-1 cells. 285 Oct 34

Monophosphoryl lipid A (MPL), a detoxified form of endotoxin, was evaluated for its ability to elicit cytotoxic factors in the serum of mice pretreated with BCG. BDF1 mice were given a priming dose of bacillus Calmette-Guerin (BCG) intravenously (i.v.). Two weeks later, these mice were challenged with MPL i.v. and their serum was tested for cytotoxicity against Lewis lung carcinoma cells growing in culture. A well-tolerated dose of MPL induced substantial serum cytotoxic activity comparable to that found after a toxic dose of endotoxin. The effective dose of MPL for eliciting serum cytotoxicity was 20 times less than the toxic dose of MPL in BCG-primed mice. No serum cytotoxicity was induced by MPL without prior treatment with BCG or in mice exposed to BCG for less than 10 days. The i.v. route of administration was superior to intraperitoneal, intrapleural, or subcutaneous routes for both BCG priming and induction of serum activity with MPL. Serum manifested TNF-like activity in that it was heat-stable, not species-specific, more effective against tumor than normal cell lines, and more effective against a TNF-sensitive than a TNF-resistant cell line. We conclude that MPL is an effective, well-tolerated biological response modifier that triggers production of cytotoxic factors in serum of mice with an activated reticuloendothelial system.
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PMID:Endogenous production of cytotoxic factors in serum of BCG-primed mice by monophosphoryl lipid A, a detoxified form of endotoxin. 337 36

Recombinant human tumor necrosis factor (rHu-TNF) was found to exhibit potent antitumor activities not only against murine tumors, i.e. Meth A sarcoma, B 16 melanoma, colon 26 adenocarcinoma, Lewis lung carcinoma and MH134 hepatoma, transplanted in syngeneic mice but also against human tumors, i.e. HMV-2 melanoma, PC-10 lung carcinoma and GOTO neuroblastoma, heterotransplanted in nude mice. rHu-TNF caused necrosis of all tumors tested and inhibited their growth in a dose dependent manner. Complete regression of tumors was observed in mice bearing Meth A, B16, colon 26, MH134, HMV-2 and PC-10 but not in mice bearing Lewis lung carcinoma and GOTO neuroblastoma. The prolongation of survival time was also observed in syngeneic mice transplanted with murine tumors except Lewis lung carcinoma. The antitumor effect of rHu-TNF was more evident when it was given intratumorally than when given intravenously. The feasibility of rHu-TNF as a drug for cancer therapy is discussed.
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PMID:Recombinant human tumor necrosis factor--II. Antitumor effect on murine and human tumors transplanted in mice. 352 34

The possibility that production of some cytokines in the carcinoma microenvironment is associated with the presence and differentiation of cells belonging to the dendritic cell (DC)/Langerhans' cell (LC) lineage was investigated. Immunohistochemical examination showed the presence of intraepithelial LCs (CD1a- and S100-positive cells) in 6 of 10 squamous cell carcinomas and in 8 of 10 adenocarcinomas. Langerhans' cells were mainly located close to lymphoid aggregates. In situ hybridization performed in four cases (three LC positive and one LC negative) of squamous cell carcinoma and in five cases (four LC positive and one LC negative) of adenocarcinoma showed that some mononuclear cells in the interstitium displayed hybridization with granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and interleukin 1-beta (IL1 beta) cDNA probes. Only in LC-positive carcinomas did epithelial cells close to lymphoid aggregates display small amounts of GM-CSF and TNF alpha mRNA expression. Immunohistochemical analysis performed in the 20 cases of lung carcinoma showed that epithelial cells in tumors with lymphoid aggregates and LCs were immunoreactive with antihuman GM-CSF monoclonal antibody. Specimens negative for GM-CSF contained very few LCs. Northern blot analysis was used to investigate GM-CSF, TNF alpha, IL1 alpha, and IL1 beta mRNA expression in six human lung carcinoma cell lines. A constitutive expression of TNF alpha mRNA was found in all of them, whereas only three showed a low constitutive expression of GM-CSF mRNA. In the latter three cell lines treatment with phytohemagglutinin (PHA)-stimulated peripheral blood lymphocyte (PBL) supernatant (PHA-SUP) upregulated GM-CSF mRNA expression and induced that of IL1 alpha mRNA. Carcinomatous epithelial cells producing small amounts of cytokines could promote the recruitment of cells of DC/LC lineage. Subcellular factors produced by reactive lymphocytes and/or macrophages may influence the production of GM-CSF and IL1 alpha by various epithelia. Up-regulation of this production could favor the arrival and differentiation of DCs and activate LC functions.
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PMID:Role of cytokines in distribution and differentiation of dendritic cell/Langerhans' cell lineage in human primary carcinomas of the lung. 763 48

5'-deoxy-5-fluorouridine (5'-FUdR) is a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by pyrimidine nucleoside phosphorylase (PyNPase), the expression of which is up-regulated by tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma). In Lewis lung carcinoma (LLC) cell cultures, these inflammatory cytokines up-regulated the expression of type-IV collagenase, metastatic factor, as well as PyNPase and consequently enhanced the antiproliferative activity of 5'-FUdR. However, the activity of 5-FUra was not enhanced. It appears that 5'-FUdR selectively kills highly metastatic cells which are exposed to these intrinsic cytokines in tumor tissues, because of their high PyNPase activity. In fact, 5'-FUdR inhibited the spontaneous metastasis of LLC from the s.c. inoculation site to the lung. When 5'-FUdR was given during the process of metastasis it greatly reduced the number of tumor nodules in the lung even at doses 46 times lower than those inhibiting the primary tumor growth. In addition, 5'-FUdR, but not 5-FUra, lowered type-IV collagenase levels in the tumors at the low dose showing only anti-metastatic activity. On the other hand, 5-FUra showed anti-metastatic activity at doses similar to or only several times lower than those inhibiting the primary tumor growth.
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PMID:Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. 775 57

Macrophages from mice bearing Lewis lung carcinoma release higher amounts of C3 molecules than macrophages from healthy mice. The C3 pro-releasing activity operating in vivo was suspected to be due to an immunological network. Indeed, the supernatants of splenocytes from tumor bearing mice, but not from normal mice, induced in vitro an increased release of C3 molecules by macrophages. Recombinant IFN gamma and TNF alpha were strong inducers of C3 release, while IL-2 acted poorly. The C3 pro-releasing activity of splenocyte supernatants was largely prevented by their pretreatment with specific mAb anti IFN gamma or anti TNF alpha, but not completely prevented by the simultaneous neutralization of the two cytokines. Taken together, these results show that murine macrophages increase the release of C3 molecules upon treatment with IFN gamma or TNF alpha and that these cytokines released in vivo by splenocytes from tumor bearing mice may account, together with a yet unknown factor, for a humoral network causing the increased release of C3 by peritoneal macrophages.
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PMID:IFN gamma and TNF alpha cause an increased release of C3 by murine macrophages. 789 Mar 16

By secreting granulocyte/macrophage colony-stimulating factor (GM-CSF), metastatic Lewis lung carcinoma (LLC-LN7) tumors induce the appearance of myelopoiesis-associated immune-suppressor cells that resemble granulocytic-macrophage (GM) progenitor cells. The presence of these GM-suppressor cells in mice bearing LLC-LN7 tumors was associated with a reduced capacity of splenic T cells to proliferate in response to interleukin-2 (IL-2). Administration of low doses of 100 U interferon gamma (IFN gamma) plus 10 U tumor necrosis factor alpha (TNF alpha) to the tumor bearers, a combination treatment that we previously showed to diminish the presence of GM-suppressor cells synergistically, restored proliferative responsiveness of the splenic T cells to IL-2. These LLC-LN7-bearing mice were also examined for whether cells that phenotypically resemble GM-progenitor cells (ER-MP12+ cells) infiltrate the tumor mass. ER-MP12+ cells composed approximately 10% of the cells isolated from dissociated tumors of mice that had been treated with placebo or with either IFN gamma or TNF alpha alone, but IFN gamma/TNF alpha therapy markedly reduced the number of tumor-infiltrating ER-MP12+ suppressor cells. The IFN gamma/TNF alpha treatment to eliminate GM-suppressor cells and restore T cell responsiveness to IL-2 was next coupled with low dose IL-2 therapy (100 U twice daily). Addition of IL-2 to the treatment regimen did not significantly influence the effectiveness of the IFN gamma/TNF alpha treatment in eliminating GM-suppressor cells from the LLC-LN7 tumor mass. However, inclusion of IL-2 with the IFN gamma/TNF alpha treatment regimen enhanced the CD8+, but not the CD4+, cell content within the tumor, and diminished the number of metastatic lung nodules within the mice. When these tumors were excised, dissociated, and bulk-cultured with a low dose of IL-2, an increased level of cytotoxic T lymphocyte (CTL) activity was generated in the TIL cultures from mice that had received IFN gamma/TNF alpha plus IL-2 treatments. A lesser but detectable level of CTL activity was generated in TIL cultures from mice that were treated with only IFN gamma/TNF alpha, while no CTL activity was generated in tumor cultures from mice receiving only placebo or low-dose IL-2. These results suggest the effectiveness of IFN gamma plus TNF alpha therapy in restoring IL-2 responsiveness in mice bearing GM-suppressor cell-inducing tumors and at enhancing both the intratumoral CD8+ cell content and the generation of CTL activity in bulk cultures of these tumors.
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PMID:Increasing infiltration and activation of CD8+ tumor-infiltrating lymphocytes after eliminating immune suppressive granulocyte/macrophage progenitor cells with low doses of interferon gamma plus tumor necrosis factor alpha. 829 23


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