Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An H-2Kb- negative clone of BL6 melanoma (BL6-8) was transfected with neor, H-2Kb, or H-2IAk genes. In an 18-h cytotoxicity assay clones with high levels of H-2Kb Ag expression were found more sensitive to lysis by spleen cells of syngenic and allogeneic mice than H-2Kb low clones. NK cells were involved in the lysis of H-2Kb+ BL6 melanoma clones, with spleen cell cytotoxicity of mice increased after poly I:C stimulation or decreased after pretreatment with anti-asialo GM1 serum or NK1.1 mAb. Anti-TNF Ab were also able to reduce the cytotoxicity of normal spleen cells and completely abolished the cytotoxicity of the NK-depleted spleen cells suggesting involvement of NC cells in lysis of H-2Kb+ BL6 melanoma clones. Increase in sensitivity of H-2Kb+ BL6 cells to natural cell-mediated cytotoxicity was associated with the appearance of NK recognizable determinants as assessed by the cold target inhibition assay. All BL6 clones, irrespective of sensitivity to natural cell-mediated cytotoxicity, showed high sensitivity to lysis by LGL-derived granules. In contrast, all H-2Kb low BL6 clones were resistant and all H-2Kb highly positive clones were sensitive to lysis by TNF-alpha. When an H-2Kb highly positive clone was selected in vitro for resistance to TNF, it concomitantly showed increased resistance to cytotoxicity by spleen cells, confirming the importance of TNF in spleen cell cytotoxicity against H-2Kb+ melanoma cells. Taken together, the data indicate that class I H-2Kb but not class II H-2IAk gene product could increase the sensitivity of BL6 cells to lysis by NK and natural cytotoxic cells as well as TNF. We hypothesize that these effects could be due to pleiotropic effects of H-2Kb gene products on various biologic properties of BL6 melanoma cells some of which may be more directly involved in regulation of tumor cell sensitivity to lysis by NK and/or natural cytotoxic cells.
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PMID:Increased sensitivity to MHC-nonrestricted lysis of BL6 melanoma cells by transfection with class I H-2Kb gene. 238 72

The growth of the murine myelomonocytic leukemia tumor, WEHI-3B, has been shown to be inhibited by a two-step treatment: first, incubation for one hour with either interleukin-1 (human recombinant IL-1 alpha or tumor necrosis factor (human recombinant TNF-alpha); second, subsequent exposure to prostaglandins. Preincubation with IL-1 rendered the tumor cells more susceptible to subsequent treatment with either prostaglandin E2 or to the stable synthetic analogue of prostacyclin DC-PGI2. Preincubation with TNF-alpha rendered the tumor cells more susceptible to further treatment with PGE2 but not with DC-PGI2. Preconditioning of the tumour cells with either IL-1 alpha or TNF alpha did not affect cytostasis by subsequent culture of tumor cells in presence of either one of the cytokines. It is concluded that the interactions between macrophage cytokines and prostaglandins in enhancement of antitumor activity might imply first binding or induction of certain modifications in the tumor cells by the cytokines which render the cells more susceptible to exposure to prostaglandins.
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PMID:Macrophage cytokines render WEHI-3B tumor cells susceptible to cytostasis by prostaglandins. 238 15

Monoclonal antibodies were produced against two structurally related tumor necrosis factors (TNFs), TNF-alpha (previously called tumor necrosis factor) and TNF-beta (previously called lymphotoxin). The potential of these antibodies for the purification of TNFs, the development of specific immunoassays, and for defining the antigenic and functional domains of these cytokines was investigated. None of the monoclonal antibodies cross-reacted with both TNF-alpha and TNF-beta, or reacted with synthetic peptides which represented several of the regions of homology between these cytokines. Neutralizing monoclonal antibodies were utilized as immunoadsorbents to purify recombinant TNF-alpha and TNF-beta from E. coli lysates. TNFs purified by this method were greater than 98 percent pure by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and exhibited specific activities that were the same as TNFs isolated from natural sources using conventional chromatographic techniques. In addition, specific ELISA assays were developed that could detect less than 1 ng/ml of TNF-alpha or TNF-beta, and in contrast to bioassays, could discriminate between these related cytokines.
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PMID:Monoclonal antibodies to human tumor necrosis factors alpha and beta: application for affinity purification, immunoassays, and as structural probes. 244 55

The oncolytic strain 73-T of Newcastle disease virus (NDV) has been reported to be beneficial in the treatment of cancer patients, but little is known about its mechanism of action. In this study, NDV strain 73-T and a wild-type isolate of NDV were found to be potent inducers of tumor necrosis factor (TNF) production by both human peripheral blood mononuclear cells (PBMCs) and rat splenocytes. Antibody inhibition experiments identified TNF-alpha as the major species of TNF induced by NDV in PBMCs. The effect of recombinant human TNF-alpha (rHuTNF-alpha) on human cancer cells was then examined. Neither rHuTNF-alpha nor supernatants from NDV-stimulated PBMCs were cytotoxic toward the TNF-resistant human malignant melanoma cell line MEL-14. However, when MEL-14 cells were treated with NDV strain 73-T, both rHuTNF-alpha and supernatants from NDV-stimulated PBMCs killed 48% and 55%, respectively, of these tumor cells. Treatment with NDV also conferred TNF susceptibility to the TNF-resistant human malignant melanoma cell line MEL-21 and the human myelogenous leukemia cell line K562. In contrast to its enhanced cytotoxicity toward NDV-treated cancer cells, rHuTNF-alpha had no effect on NDV-treated normal human PBMCs proliferating in response to concanavalin A. These results suggest two important mechanisms for the antineoplastic activity of NDV: (a) induction of TNF-alpha secretion by human PBMCs and (b) enhancement of the sensitivity of neoplastic cells to the cytolytic effects of TNF-alpha.
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PMID:Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. 245 2

The macrophage-activating properties of murine recombinant granulocyte-macrophage (GM)-CSF were studied in murine peritoneal macrophages with respect to metabolism, endocytosis, PGE2 and TNF-alpha release, and tumor cytotoxicity. GM-CSF was found to be a potent stimulus for RNA and protein synthesis, glucose consumption, pinocytosis, and FcR-independent phagocytosis. Macrophages were activated by GM-CSF to kill TNF-alpha-insensitive Eb lymphoma cells but failed to generate cytotoxicity against TNF-alpha-sensitive L929 cells. Although GM-CSF alone was incapable of stimulating TNF-alpha release, it primed macrophages for elevated TNF-alpha production in response to IFN-gamma plus LPS. The priming effect of GM-CSF disappeared upon longer incubation (greater than 12 h) and was followed by a strongly reduced responsiveness to stimuli that release TNF-alpha. Late-stage suppression could be reverted by treatment with the cyclooxygenase blocker indomethacin, and GM-CSF-induced priming for enhanced TNF-alpha release was entirely restored. The responsible arachidonic acid product mediating suppression was found to be PGE2, because 1) GM-CSF-primed macrophages released enhanced amounts of PGE2 and 2) indomethacin-restored macrophages were again suppressed when exogenous PGE2 was added back in amounts produced by GM-CSF-primed macrophages. Although GM-CSF potently induced TNF-alpha gene transcription by 20 h of treatment, PGE2 interfered with translation into the secreted TNF-alpha protein. These data show that GM-CSF is capable of priming for the enhanced release of two factors, initially for TNF-alpha and subsequently for PGE2. The temporally delayed generation of these two mediators suggests an autoregulatory circuit in which the later produced PGE2 limits GM-CSF-induced macrophage activation.
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PMID:Macrophage activation by granulocyte/macrophage colony-stimulating factor. Priming for enhanced release of tumor necrosis factor-alpha and prostaglandin E2. 247 21

In vitro macrophage- or TNF-alpha-mediated selection procedures on 3LL tumor cells have led to the selection of 3LL variants manifesting a highly reduced sensitivity towards the cytotoxic effects of both TNF-alpha and tumoricidal macrophages, while retaining the parental sensitivity to the cytolytic activity of (i) H2O2, (ii) macrophage-ADCC reactions and (iii) NK cells. A correlation was observed between the TNF-alpha binding capacity of the 3LL cell lines and their susceptibility towards macrophage- and TNF-alpha-mediated cytotoxicity, indicating that macrophage and TNF-alpha sensitivity may partially be regulated at the TNF-alpha receptor level. Further, the selected 3LL variants are gene-regulatory variants rather than cellular mutants, as upregulation of the TNF-alpha receptor by interferon-gamma (IFN-gamma) or 5'-azacytidine treatment resulted in an increased vulnerability of the selected 3LL variants to the killing activity of macrophages and TNF-alpha. The resistance of the 3LL variants to macrophage- and TNF-alpha-mediated cytotoxicity in vitro was reflected by a higher tumorigenic and metastatic potential in vivo. Therefore, the generation of TNF-alpha- and macrophage-resistant variants through immunoselection may contribute to the basic mechanisms of tumor progression and metastasis.
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PMID:TNF-alpha mediated selection of macrophage-resistant gene-regulatory tumor variants. 247 62

The production of interferons (IFNs), IFN-gamma, tumor necrosis factors (TNFs) and TNF-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMNCs) of untransfused and transfused, but otherwise untreated patients with severe aplastic anemia (SAA) was determined using bioassays and immunoassays. In untransfused and pretransfused SAA patients, spontaneous and lectin-induced production of these cytokines by PBMNCs was strongly enhanced. Cytokine production in untransfused SAA patients did not differ from that in pretransfused patients. Similar relative frequencies of activated (HLA-DR+) lymphocyte subpopulations present in the PBMNCs demonstrated cytokine overproduction per cells. Cytokine production was studied in three SAA patients before and after blood cell transfusions. Spontaneous and lectin-induced production of these cytokines was abnormally high and unaffected by blood transfusions. In another patient exhibiting abnormal cytokine production, the hematopoietic response to cyclosporin-A in vivo was accompanied by normalization of cytokine production in vitro. We conclude that overproduction of IFN-gamma and TNF-alpha by lectin-stimulated PBMNCs is an intrinsic abnormality of SAA unrelated to blood transfusions. Normalization of production of IFN-gamma and TNF-alpha accompanying a clinical response to cyclosporin-A may cautiously be taken as further evidence suggesting a pathogenetic role of cytokine overproduction in SAA.
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PMID:Lymphokine overproduction in severe aplastic anemia is not related to blood transfusions. 247 29

Immunotherapy with interleukin 2 (IL-2) alone or in combination with lymphokine-activated killer cells can mediate tumor regression in mice and in man. Further dose escalation of IL-2 along with lymphokine-activated killer cells has been prevented by the development of a vascular leak syndrome produced by IL-2. Because we have found that interferon alpha (IFN-alpha) or tumor necrosis factor (TNF-alpha) has synergistic antitumor effects when administered together with IL-2, we have tested the vascular leakage induced by these lymphokine combinations. We used a murine model to quantify vascular leakage by measuring the extravasation of 125I-albumin from the intravascular space as well as the wet and dry lung weights after treatment with different cytokines. Cytokines (or Hanks balanced salt solution) were administered to C57BL/6 mice and 4 h after the last injection the vascular leak was quantified. IFN-alpha alone did not cause extravasation of radiolabel or increase in wet lung weights, though when given in combination with IL-2, significantly greater extravasation (P less than 0.01) as well as increase in lung water weights (P less than 0.05) was observed compared to the response in mice treated with IL-2 alone. IFN-alpha in combination with IL-2 induced significant vascular leakage earlier than the response induced by IL-2 alone. For example treatment with IFN-alpha and IL-2 induced accumulation of 14,674 +/- 605 cpm in the lungs at day 1 while IL-2 alone induced 12,340 +/- 251 cpm. The degree of vascular leakage was highly related to the dose of IFN-alpha administered along with IL-2 and increased vascular leak syndrome was evident even at low doses (5000 units) of IFN-alpha. Immunosuppression of mice by pretreatment irradiation (500 rad) markedly decreased the development of vascular leak syndrome induced by IL-2 and IFN-alpha. Interestingly IFN-gamma and TNF-alpha did not induce vascular leakage in the lungs when given alone, and did not add or synergize with IL-2 in causing the syndrome. Thus the administration of IFN-alpha in combination with IL-2 produces a dose-limiting vascular leakage that is more severe than that caused by IL-2 alone, and may be mediated, directly or indirectly by host radiosensitive cells.
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PMID:Combined effects of interferon alpha and interleukin 2 on the induction of a vascular leak syndrome in mice. 249 79

This investigation was undertaken in order to assess both the preventive and antiproliferative effects of tumor necrosis factor (TNF) in a hepatic metastasis model, by means of inoculation of mouse colon-26 tumor cells into the portal vein via the superior mesenteric vein in male CDF1 mice, aged 5 weeks. Continuous 10-day administration of natural human TNF-alpha (nHuTNF-alpha) following the tumor cell inoculation caused no reduction but rather an increase in the number of hepatic metastases. However, pretreatment with this preparation daily for 10 days before the inoculation caused a remarkable decrease in the number of hepatic metastases. This prophylactic effect was reversed by the intravenous administration of anti-asialo GM1 antibody 24 h before the inoculation. The result of immunoperoxidase staining of liver specimens suggested that organ-associated natural killer cells might play a role in the metastatic inhibition. An apparent antiproliferative effect on metastatic liver tumors was also recognized following injection of nHuTNF-alpha from the 10th day after the inoculation. Thus, TNF appears to have important effects upon the host immune system, acting against liver metastases.
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PMID:Preventive and antiproliferative effects of tumor necrosis factor against experimental hepatic metastases of mouse colon-26 tumor. 250 Dec 53

Sensitivity of cultured choriocarcinoma cell lines to tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma was examined and compared with that of other cultured tumor cell lines. Tumor cells were cultured with 1,000 mu/ml of TNF-alpha and/or 100 mu/ml of IFN-gamma for 24hr. Antitumor effects of the lymphokines were measured by 3H-thymidine uptake and tetrazolium salt (MTT) colorimetric assay. The results revealed that TNF-alpha and/or IFN-gamma had little anti-tumor effect on the choriocarcinoma cell lines tested, while they had cytostatic and cytotoxic effects on other cultured tumor cell lines including Panc-1 (pancreatic carcinoma cell line), Lovo (colon carcinoma cell line) and Ishikawa (uterine endometrial carcinoma cell line). We also examined the effect of TNF-alpha and IFN-gamma on the expression of major histocompatibility complex (MHC) class I antigens in these tumor cell lines by means of cellular binding radioimmunoassay. No enhancing effect was observed on choriocarcinoma cell lines after the treatment with TNF-alpha and/or IFN-gamma. These results suggested the existence of a unique property of choriocarcinoma cells which results in the resistance to host immune attacks.
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PMID:[Low sensitivity of choriocarcinoma cell lines to tumor necrosis factor (TNF)-alpha]. 250 46


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