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)

Activated granulocytes play an important role in propagation of the inflammatory response by production of reactive oxygen species and release of their granule content. Hyperactivation of these cells is suggested to result in deterioration of wound healing and, probably, increase of cicatrization. Pantothenic acid and its stable salt form, Ca-Panthotenate, were shown to significantly improve surgical wound healing. Therefore, in the present study the modulating effect of Ca-pantothenic acid to subsequent stimulation with a variety of stimuli was investigated on isolated human PMN using functional assay systems: Lucigenin-dependent chemiluminescence (CL), release of myeloperoxidase (MPO). Ca-Panthotenate significantly inhibited the CL response of PMN upon stimulation with the chemotactic petide f-met-leu-phe, the tumor promotor PMA, and the granulocyte activating cytokines GM-CSF and TNF alpha at a concentration range of 5 to 50 mM, but not upon stimulation with opsonized zymosan. Moreover, Ca-Panthotenate significantly inhibited the release of myeloperoxidase from PMN upon stimulation with f-met-leu-phe at a concentration of 5 mM. In contrast, Ca-Panthotenate did not directly activate PMN in the assay systems tested. These in vitro results support the concept of an anti-inflammatory action of Ca-Panthotenate in vivo.
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PMID:Effect of Ca-panthotenate on human granulocyte oxidative metabolism. 166 12

In response to virus induction a culture of donor leukocytes alongside with interferon (IF-alpha) produced a factor of tumor necrosis (TNF). The kinetics of TNF and IF-alpha biosynthesis did not depend on the kind of IF used for priming, was rapid, with maximum production within 7-8 hours. Antibodies to IF-alpha and IF-alpha had no effect on TNF production, while antibody to TNF did not reduce IF-alpha yields. TNF in detectable titres was present in medical preparations of native IF-alpha but was absent in preparations of recombinant IF-alpha and IF-alpha as well as in an injection preparation of IF purified by chemical methods.
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PMID:[Tumor necrosis factor in medicinal interferon preparations]. 166 19

Platelet-activating factor (PAF) is a low molecular weight phospholipid which enhances human monocyte cytotoxicity for tumor cells. In the current studies, the capacity of PAF to stimulate release of tumor necrosis factor alpha (TNF alpha) by human monocytes was assessed. PAF induced maximal TNF alpha synthesis 2-3 hr after monocyte stimulation as assessed by dot blotting of cell-associated TNF alpha using polyclonal anti-TNF antibody. Maximal net release of TNF alpha occurred 5-16 hr after monocyte stimulation, as assessed by a specific ELISA. Dose-response studies revealed that a maximal two- to three-fold increase in release of TNF alpha occurs at 10-100 pM PAF. LysoPAF and the optical isomer of PAF did not stimulate release of TNF alpha, suggesting that stimulation is mediated by specific PAF receptors. Scatchard analysis of [3H]PAF binding to monocyte membranes revealed 651 +/- 495 binding sites/monocyte with a Kd of 4.7 +/- 4.2 x 10(-10) M. PAF is a structurally unique activator of monocytes whose interactions with TNF alpha and other cytokines may be critical to host defense against tumors.
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PMID:Tumor necrosis factor release by human monocytes stimulated with platelet-activating factor. 166 5

Four human ovarian and breast tumor lines expressing the HER2/neu oncogene were resistant to the cytotoxic and DNA-degradative activity of TNF. The resistance was not associated with altered TNF receptor function because Scatchard analysis of 125I-rTNF binding to HER2/neu-expressing target cells revealed receptors with normal binding parameters. Furthermore, the TNF receptors on the resistant lines were capable of signal transduction as evidence by the induction of ADP-ribose polymerase activity and MHC expression. TNF resistance was not reversed by coincubation with drugs that interrupted the glutathione redox cycle. In addition, although coincubation of HER2/neu-expressing targets with cycloheximide resulted in significant TNF-induced lysis, when compared to HER2/neu-nonexpressing targets similarly treated with cycloheximide, a significant relative resistance was still present. To investigate the role of ADP-ribosylation in the resistance of these targets, we used nontoxic concentrations of two inhibitors of ADP-ribose polymerase, 3-aminobenzamide, and nicotinamide. Both inhibitors completely reversed the resistance of HER2/neu-expressing targets to TNF-mediated cytotoxicity and DNA injury in a concentration-dependent fashion. These inhibitors of ADP-ribose polymerase did not act by down-regulating expression of HER2/neu oncogenes. In contrast, aminobenzamide and nicotinamide significantly diminished TNF-induced cytotoxicity of L929 targets. These data suggest that the activity of ADP-ribose polymerase may play a pivotal role in determining the fate of the target cell during exposure to TNF.
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PMID:Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu-expressing cancer cells to the cytotoxic effects of tumor necrosis factor. 167 41

Pretreatment of the human melanoma cell line, A375, and the human colon carcinoma cell line, HT-29, with certain cytokines was found to increase the vulnerability of these cells to monocyte-mediated killing. This activity was found to correlate with increased expression of intercellular adhesion molecule-1 (ICAM-1) on the tumor cells and was blocked by anti-ICAM-1 antibodies. Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. IFN-alpha and IL-1 beta, however, induced only small increases in ICAM-1 expression and enhanced the lysis of the A375 cells but not the HT-29 cells by monocytes. These differences may be the result of a higher basal expression of ICAM-1 found on the A375 cells when compared with the HT-29 cells. These data indicate that regulation of ICAM-1 expression on tumor cells can alter the vulnerability of these cells to lysis by monocytes.
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PMID:Cytokine-induced enhancement of ICAM-1 expression results in increased vulnerability of tumor cells to monocyte-mediated lysis. 167 88

Appropriately activated mononuclear phagocytes mediate contact-dependent tumoricidal activity. Adhesion structures involved in contact-dependent tumor cytotoxicity have not been defined. The present study was aimed at identifying the adhesion structures involved in the tumoricidal activity of activated (IFN-gamma + LPS) human monocytes. Tumor cells of different histological origin were used as targets in a 48-hr cytolysis assay. Anti-CD18 (integrin beta 2 chain) monoclonal antibodies (MAbs) substantially (50-80%) inhibited human monocyte cytotoxicity. When the role of different a-chains was studied, anti-alpha L (CD11a, LFA1), anti-alpha M (CD11b, Mac-1) and anti-alpha X (CD11c, p150,95) caused marginal inhibition, but the effect of the 3 combined was comparable to that of anti-CD18. Anti-CD18 MAb did not affect the release of various cytotoxic molecules (e.g. TNF) by activated human monocytes. Activated monocytes showed augmented binding to target cells and anti-CD18 MAb inhibited the binding of resting and activated monocytes to tumor target cells. While IFN-gamma alone augmented expression of leukocyte integrins and LPS had no effect, the 2 activation signals, combined for optimal stimulation of tumoricidal activity, resulted in no appreciable increase in these leukocyte adhesion molecules, as assessed by flow cytometry. Our results suggest that the augmented CD18-dependent binding of activated monocytes on tumor cells depends mainly upon changes in the adhesive properties of these molecules rather than upon increased numbers on the cell surface. Anti-ICAM-1 MAb significantly reduced monocyte cytotoxicity on tumor cells, which is consistent with a role of the CD11/CD18 adhesion pathway. These results implicate "activated" leukocyte (beta 2) integrins (CD11/CD18) as important adhesion molecules in the contact-dependent tumoricidal activity of human monocytes.
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PMID:Involvement of leukocyte (beta 2) integrins (CD18/CD11) in human monocyte tumoricidal activity. 167 46

A novel cytotoxicity, which is normally hidden but unveiled upon interacting with heat-shocked tumor target, has been identified in CD4+ Th1 cells. When TNF-resistant, Ag-presenting tumor targets were heat shocked, the cytotoxicity by specific Th1 clones was significantly enhanced. Interestingly, the DNA of heat-shocked, unpulsed targets including Ia- tumor cells were also fragmented by Th1 clones. In contrast to the Ag-dependent, MHC-restricted cytotoxicity, the heat-shock-induced sensitivity to Th1 clones was a) Ag independent and MHC unrestricted, b) insensitive to CD4-mAb, c) resistant to actinomycin D and cycloheximide, and d) greatly enhanced by cholera toxin, PGE1, PGE2, and dibutyryl cAMP. This novel cytotoxicity was inhibited by mAb specific to lymphocyte function-associated Ag-1 and intercellular adhesion molecule-1. Upon culturing at 37 degrees C, mildly heat-shocked target cells gradually recovered, indicating that the heat-shock-induced sensitivity was transient and reversible. The implication of this study for a signal-induced internal disintegration mechanism for target death is discussed. The novel cytotoxicity of CD4+ Th1 cells may be an important mechanism of immune regulation under febrile conditions and an underlying mechanism for the hyperthermia treatment of cancers.
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PMID:A novel cytotoxicity of CD4+ Th1 clones on heat-shocked tumor targets. I. Implications for internal disintegration model for target death and hyperthermia treatment of cancers. 168 89

In this study we demonstrate that tumor necrosis factors (TNF alpha and TNF beta) are potent modulators of the in vitro proliferation of human AML cells. Blast cells from 11 cases of acute myeloblastic leukemia (AML) were incubated with recombinant TNF alpha or TNF beta in serum-free 3H-TdR uptake and colony culture systems in the presence or absence of recombinant interleukin-3 (IL-3), granulocyte macrophage colony-stimulating factor (GM-CSF), G-CSF, or M-CSF. Depending on the supplemented CSF, TNF could upregulate or suppress AML blast proliferation. Enhancement of AML growth by TNF was observed in the presence of IL-3 (in 9 of 11 cases in 3H-TdR assay; 6 of 9 cases in colony assay) and GM-CSF (in 8 of 11 cases in 3H-TdR assay; 4 of 9 cases in colony assay). In certain cases in which IL-3 or GM-CSF alone was unable to induce proliferative responses of AML cells, the simultaneous addition of TNF elicited colony growth and DNA synthesis suggesting a synergistic action between TNF and IL-3 or GM-CSF. In contrast, TNF suppressed G-CSF-induced growth (9 of 10 cases in 3H-TdR assay; 5 of 6 cases in colony assay). TNF could also stimulate DNA synthesis (in 2 of 11 cases) or colony formation (in 2 of 9 cases) in AML cultures without the addition of other growth factors. Experiments with neutralizing antibodies and specific radioimmunoassays for individual CSFs showed that the synergistic and antagonistic effects of TNF on AML growth could not be attributed to a release of one of these CSFs by the AML cells. The opposing consequence of exposure of AML blasts to TNF are of interest in view of our understanding of the pathophysiology of AML growth and the in vivo application of recombinant cytokines in AML patients.
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PMID:Modulation of colony stimulating factor-(CSF) dependent growth of acute myeloid leukemia by tumor necrosis factor. 168 38

Three modes of receptor-mediated cancer therapy were reviewed presenting our own data. Employment of tumoricidal cytokines (IFN, TNF, LT) to this type of therapy has been expected to be the most promising approach. However, preclinical and clinical results so far obtained, revealed that they were useful only for the very limited diseases including renal cancer or some hematological malignancies. Second approach is to utilize growth factors conjugated with toxin or carzinostatin which are readily internalized into tumor cells. In this context, transferrin-neocarzinostatin was examined in our laboratory both in vitro and in vivo for its anticancer activity and was found to suppress tumor growth more significantly than neocarzinostatin alone on the basis of molar ratio. Thus this approach may be worthy to be clinically investigated. Adoptive therapy of lymphokine activated killer (LAK) or tumor infiltrating lymphocyte (TIL) may also be categorized into receptor mediated cancer treatment since both are activated by signals through IL-2 receptor. Although clinical evaluation is still on going, the therapy appears to be effective only when effector cells are administered locally to tumors.
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PMID:[Receptor-mediated cancer therapy--tumoricidal cytokines, adoptive therapy of LAK, TIL]. 169 87

Deterioration in nutritional status occurs late in the progress of cancers at certain sites, but at all stages in patients with gastrointestinal cancer. Weight loss with decrease in body fat and muscle wastage, occurs to a varying degree. Superficially, the clinical condition resembles simple food deprivation. However, the derangements in metabolism are often and some patients show an elevated resting energy expenditure, disturbances of carbohydrate, fat and protein metabolism and generally, a failure to adapt to reduced food intake, which is characteristic of cachexia. Cancer cachexia then becomes characterized by signs of marked negative energy and protein balance, including hypoalbuminemia, weight loss, and anemia. On the other hand, toxohormone extracted from tumor tissues was considered as the main cause to produce cancer cachexia. However, it has become clearer that cytokines, e.g. cachectin/TNF, IL-1, LT and IFN gamma play an important role to produce cachexia. Patients who are malnourished have an incidence of postoperative complications double that seen in adequately nourished patients. The effectiveness of cancer-chemotherapy is also different in nutritional status of patients. Although in patients requiring hyperalimentation, enteral nutritional support may feasible and enteral feeding has a distinct metabolic advantage compared with parenteral feeding, there is a definite role for total parenteral nutrition in patients who have severe chronic radiation enteritis, side effect of chemotherapy, weight loss and malabsorption. Tentative weight gain and correction of hypoalbuminemia without improving patient survival may be expected by this intravenous hyperalimentation.
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PMID:[Palliative therapy in cancer 2. Nutrition control]. 169 91


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