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

Monoclonal antibodies have been raised against a dimeric cell surface antigen (p75/150) which is specifically associated with the tumorigenic phenotype in human fibroblast X HeLa hybrids. During biosynthesis, a precursor molecule (p70/140), was associated with microsomal membranes in vivo but possessed no detectable cytoplasmic domains. At this stage, each p70 monomer contained 3 "high-mannose" type N-linked glycans which were subsequently processed into endoglycosidase H-insensitive complex oligosaccharides on the mature cell surface forms. Cleavage of this cell surface form with endoglycosidase F yielded non-N-glycosylated polypeptides of Mr = 60,000/120,000. All the monoclonal antibodies identified similar non-N-glycosylated polypeptides in cells grown in the presence of tunicamycin. p75/150 could be weakly labeled with [3H]palmitic or myristic acid. In vivo, p75/150 was found to be phosphorylated on serine residues. Immunoprecipitates of p75/150 from HeLa or tumorigenic hybrid cell lysates exhibited protein kinase activity in vitro, which phosphorylated p75/150 itself, also on serine residues. We were unable to detect this kinase activity in normal fibroblasts and in the nontumorigenic hybrid cells. Furthermore, we were unable to detect p75/150 or its precursors by either cell surface labeling, metabolic labeling, or Western blotting in nontumorigenic cell hybrids; p75/150 thus represents a tumor-specific marker in this system. Tryptic peptides of highly purified p75/150 have been generated, but their amino acid sequences did not reveal any significant homology with previously described proteins.
 ...
PMID:Structural and functional features of a cell surface phosphoglycoprotein associated with tumorigenic phenotype in human fibroblast x HeLa cell hybrids. 308 Apr 34

The major species of tyrosine protein kinase of rat liver, has been purified to near homogeneity from liver cytosol. When the kinase was incubated with MnCl2 and [gamma-32P]ATP, two phosphoproteins with molecular masses of 72 and 75 kilodaltons were observed. The purified kinase, called p75 kinase, phosphorylates [Val5]angiotensin II, casein, vinculin, and a 34-kilodalton protein isolated from chicken embryo fibroblasts. However, it does not phosphorylate histones or IgG from Rous sarcoma virus tumor-bearing rabbits. The kinase does not contain any of the major antigenic determinants found in retroviral tyrosine protein kinases or in epidermal growth factor-receptor kinase. p75 kinase activity, as well as viral tyrosine protein kinase activity, is stimulated by heparin. Phosphorylation of angiotensin is also stimulated by high ionic strength. In contrast, casein phosphorylation by the kinase appeared to be inhibited by high salt. Kinetic properties of p75 kinase have been determined and have revealed some striking differences from those of most other tyrosine protein kinases. For instance, p75 kinase exhibits rather stringent dependence for its activity on ATP as phosphoryl donor and Mn2+ as divalent cation.
 ...
PMID:Purification and characterization of the major species of tyrosine protein kinase in rat liver. 653 79

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.
 ...
PMID:Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity. 754 21

The control of expression of MHC class II molecules on antigen-presenting cells is important for the induction of immunity, while aberrant expression of these molecules plays a role in the immunopathology of autoimmune diseases. This study explored the role of tumor necrosis factor alpha (TNF) in controlling the level of HLA class II mRNA in human monocytes. Exposure of monocytes to exogenous recombinant TNF (rTNF) selectively up-regulated DR alpha-mRNA but not DP or DQ alpha-mRNA. Inhibitors of TNF synthesis, pentoxifylline (PTX) and thalidomide, inhibited TNF mRNA accumulation in LPS-activated monocytes and down-regulated DR mRNA but not DP or DQ mRNA. The inhibitory effect of anti-TNF monoclonal antibody (MAb) indicated that endogenously generated TNF acted extracellularly. Anti-p75 TNF-R2 receptor and to a lesser extent anti-p55 TNF-R1 MAbs inhibited TNF-mediated up-regulation of DR mRNA and TNF mRNA. Taken together, this implies that endogenously generated TNF plays a role in controlling isotype-specific MHC class II gene expression in human monocytes/macrophages. These results may have some implications for anti-tumor response and autoimmunity.
 ...
PMID:Isotype-specific regulation of MHC class II gene expression in human monocytes by exogenous and endogenous tumor necrosis factor. 759 65

The nontumorigenic HeLa x skin fibroblast hybrid cell line, CGL1, can be induced to re-express HeLa tumor-associated cell surface antigen, p75-IAP (intestinal alkaline phosphatase), with resulting neoplastic transformation, by exposure to gamma radiation. This has allowed the human hybrid system to be developed into a quantitative in vitro model for radiation-induced neoplastic transformation of human cells. Recently, several gamma-ray-induced IAP-expressing mutants (GIMs) of the nontumorigenic HeLa x skin fibroblast hybrid CGL1 were isolated and all were tumorigenic when injected subcutaneously into nude mice (Mendonca et al., Cancer Res. 51, 4455-4462, 1991). Control cell lines which were negative for p75-IAP (CONs) were also isolated from irradiated populations, and none were found to be tumorigenic. We have now begun to investigate the molecular basis of radiation-induced neoplastic transformation in this system by studying the potential genetic linkage between p75/IAP expression, tumorigenicity and damage to a putative tumor suppressor locus on fibroblast chromosome 11. Previous analysis of rare spontaneous segregants has indicated that this locus is involved in the regulation of tumorigenicity and in the expression of the HeLa tumor-associated cell surface marker intestinal alkaline phosphatase (p75-IAP) in this system. Therefore, analysis by restriction fragment length polymorphism and chromosome painting have been performed for chromosome 11, and for chromosome 13 as a control, for the p75/IAP-positive GIM and p75/IAP-negative CON cell lines. We report that in five of eight of the GIMs large-scale damage to the fibroblast chromosome 11's is evident (four GIMs have lost one complete copy of a fibroblast chromosome 11 and one GIM has both copies of fibroblast chromosome 11 heavily damaged). None of the CONs, however (0/5), have lost a complete copy of either fibroblast chromosome 11. No large-scale damage to the control chromosome 13's was detected in the GIMs or CONs. The data further suggest that both copies of fibroblast chromosome 11 contain an active locus and that radiation-induced loss of either fibroblast chromosome 11 will result in neoplastic transformation in this system. We conclude that it is the loss of a putative tumor suppressor locus on fibroblast chromosome 11 which is responsible at least in part for radiation-induced neoplastic transformation of these human hybrid cells.
 ...
PMID:Loss of a putative tumor suppressor locus after gamma-ray-induced neoplastic transformation of HeLa x skin fibroblast human cell hybrids. 759 42

Oxidative stress such as radiation can trigger the production of cytokines including tumor necrosis factor (TNF) and lymphotoxin (LT). The increased cytokine levels may in turn induce the synthesis of protein(s) that protect against subsequent killing by oxidative stress. Indeed, pretreatment of animals with TNF or LT can protect them against lethal doses of radiation and the alopecia that results from anticancer drugs. TNF or LT can specifically and selectively induce the expression of manganous superoxide dismutase (MnSOD). MnSOD, identified as one of the protective proteins, is a mitochondrial enzyme that scavenges superoxide radicals (O2-). TNF-R1 but not TNF-R2 is responsible for TNF and LT's induction of MnSOD. Paradoxically, the TNF-R1 is also the receptor that mediates the production of oxygen free radicals and apoptosis. Overexpression of MnSOD but not CuZn-SOD or EC-SOD enhances cellular resistance to radiation. Conversely, overexpression of antisense MnSOD RNA diminishes resistance. Transfection of cells with MnSOD lacking the mitochondrial matrix signal does not provide protection against radiation. However, insertion of the mitochondrial signal sequence into CuZn-SOD or EC-SOD results in significant protection. TNF or LT does not induce MnSOD in tumor cells; nor do they protect these cells against radiation. Actually, TNF or LT pretreatment can sensitize tumor cells to killing by radiation.
 ...
PMID:Protective roles of cytokines against radiation: induction of mitochondrial MnSOD. 759 9

The formation of brain metastases is an important clinical end point in patients with cancer. The brain provides a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. In the brain microcirculation, brain-metastatic tumor cells must attach to endothelial cells, respond to brain-derived invasion factors, and invade the blood-brain barrier. Neurotrophins are important brain invasion-stimulating factors in this process, and in responsive tumor cells neurotrophins can promote invasion by enhancing the production of basement-membrane-degradative enzymes (gelatinase and heparanase) capable of locally destroying the blood-brain barrier. We examined human melanoma variant lines that express low-affinity p75 neurotrophin receptor in relation to their brain-metastatic potentials. Expression of p75 in these variants occurs in the absence of expression of trkA, the gene encoding the high-affinity nerve growth factor (NGF) tyrosine kinase receptor. Brain-metastatic tumor cells can also produce factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for tumor growth factor-beta, basic fibroblast growth factor, tumor growth factor-alpha, and interleukin-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain tissues. In support of this, we found increased amounts of NGF in tumor-adjacent tissues at the invasion front of human melanoma tumors in the brain. These and other factors may determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system.
 ...
PMID:Involvement of neurotrophins and growth factors in brain metastasis formation. 765 30

The immunologic consequences of prolonged infusions of rIL-2 in doses that produce physiologic serum concentrations of this cytokine were investigated. rIL-2 in doses of 0.5-6.0 x 10(6) U/m2 per d (3.3-40 micrograms/m2 per d) was administered by continuous intravenous infusion for 90 consecutive days to patients with advanced cancer. IL-2 concentrations (25 +/- 25 and 77 +/- 64 pM, respectively) that selectively saturate high-affinity IL-2 receptors (IL-2R) were achieved in the serum of patients receiving rIL-2 infusions of 10 micrograms/m2 per d and 30 micrograms/m2 per d. A gradual, progressive expansion of natural killer (NK) cells was seen in the peripheral blood of these patients with no evidence of a plateau effect during the 3 mo of therapy. A preferential expansion of CD56bright NK cells was consistently evident. NK cytotoxicity against tumor targets was only slightly enhanced at these dose levels. However, brief incubation of these expanded NK cells with IL-2 in vitro induced potent lysis of NK-sensitive, NK-resistant, and antibody-coated targets. Infusions of rIL-2 at 40 micrograms/m2 per d produced serum IL-2 levels (345 +/- 381 pM) sufficient to engage intermediate affinity IL-2R p75, which is constitutively expressed by human NK cells. This did not result in greater NK cell expansion compared to the lower dose levels, but did produce in vivo activation of NK cytotoxicity, as evidenced by lysis of NK-resistant targets. There was no consistent change in the numbers of CD56- CD3+ T cells, CD56+ CD3+ MHC-unrestricted T cells, or B cells during infusions of rIL-2 at any of the dosages used. This study demonstrates that prolonged infusions of rIL-2 in doses that saturate only high affinity IL-2R can selectively expand human NK cells for an extended period of time with only minimal toxicity. Further activation of NK cytolytic activity can also be achieved in vivo, but it requires concentrations of IL-2 that bind intermediate affinity IL-2R p75. Clinical trials are underway attempting to exploit the differing effects of various concentrations of IL-2 on human NK cells in vivo.
 ...
PMID:Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. 767 99

Because of the severe toxicity of systemically applied tumor necrosis factor (TNF) in cancer patients, considerable efforts have been made to construct mutant TNF molecules, which retain antitumor activity, but display less toxicity. We compared tumor suppression in relation to the toxic effects of human TNF and human lymphotoxin (LT) in mice. The genes for these two cytokines were expressed in Chinese hamster ovary (CHO) cells. Intraperitoneal injection of parental and gene modified CHO cell lines producing similar amounts of biologically active TNF or LT, respectively, into nude mice showed that CHO-TNF cells killed the mice more rapidly than parental cells, but that CHO-LT tumor bearing mice lived significantly longer than mice injected with parental cells. Injection of the cells subcutaneously into severe combined immunodeficiency (SCID) mice allowed direct comparison of tumor suppression and toxic effects of the two cytokines. Both TNF and LT produced by the tumor effectively suppressed tumor growth by an indirect mechanism, LT being at least as effective as TNF. However, mice bearing CHO-TNF cells either died rapidly or developed cachexia, as shown by weight loss. In contrast, mice injected with CHO-LT cells never rapidly died and became cachectic much later than CHO-TNF cell injected animals, though serum levels of LT were higher than those of TNF. Analysis of soluble forms of TNF receptors (TNF-R1 and TNF-R2) in sera of tumor bearing mice showed that soluble TNF-R1 was downregulated in both CHO-TNF and CHO-LT, in comparison with CHO-neo cell injected mice and to normal SCID mice. The soluble form of TNF-R2 was induced by CHO cell lines. In CHO-TNF cell injected SCID mice, serum levels were significantly increased, whereas in mice injected with CHO-LT cells, serum levels of soluble TNF-R2 were decreased. Together, our results show a higher therapeutic index of LT compared with TNF.
 ...
PMID:Human lymphotoxin has at least equal antitumor activity in comparison to human tumor necrosis factor but is less toxic in mice. 774 38

Treatment of metastatic melanoma patients with an autologous vaccine modified by the hapten, dinitrophenyl (DNP), produces a striking immunological effect: the induction of clinically evident inflammatory responses in metastatic tumors. Histological examination shows these tumors to be infiltrated with T lymphocytes. We studied the expression of activation markers on those cells and compared them with matched peripheral blood lymphocytes (PBL) and with lymphocytes extracted from metastases before treatment with DNP-conjugated vaccine. The median fraction of cells that were T cells in post-vaccine tumors was 41%, as compared with 9% in pre-treatment tumors, and those T cells were predominantly CD8+ (mean CD8/CD4 ratio = 5.0). A high proportion of both pre- and post-treatment infiltrating T cells expressed HLA-DR (mean +/- SE = 48% +/- 4%), CD69 (56% +/- 7%), and ganglioside GD3 (68% +/- 5%). This distinguished them from matched PBL in which expression of those markers was significantly lower (HLA-DR = 10% +/- 2%; CD69 = 2% +/- 0.4%; GD3 = 49% +/- 4%). These changes were not accompanied by increased cell-surface expression of interleukin-2 (IL-2) receptors, either CD25 or p75, which were expressed by 1%-2% and 12% of tumor-infiltrating lymphocytes (TIL), respectively. The pattern of activation marker expression that we identified appears to be characteristic of tissue T cells with the memory phenotype. The low expression of IL-2 receptors could indicate functional impairment of TIL in situ, perhaps because of inhibitory molecules produced by melanoma cells.
 ...
PMID:Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine. 792 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>