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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biochemical effects in the livers of male rats of prolonged administration of the experimental hepatocarcinogen nafenopin, a hypolipidemic agent and peroxisome proliferator, were compared to those of another experimental liver carcinogen, phenobarbital, which acts as a neoplasm promoter. Feeding of nafenopin, 0.03 mmol/kg basal diet for up to 24 weeks increased the numbers of hepatic peroxisomes, increased catalase activity, markedly decreased cytosolic glutathione transferase activities toward two substrates, decreased cytosolic glutathione peroxidase activities toward H2O2 and two organic peroxides, and suppressed the age-related increase in gamma-glutamyl transpeptidase activity. In contrast the livers of rats fed an equimolar concentration of phenobarbital displayed increases in cytosolic glutathione transferase activities and enhancement of gamma-glutamyl transpeptidase activity but no changes in glutathione peroxidase activities. There was also an enhancement of catalase activity without apparent increase in peroxisome number. Enzyme kinetic analyses revealed that the cytosolic glutathione transferase activities toward two halogenonitrobenzene substrates were inhibited in the rats fed nafenopin and displayed elevated Km and decreased Vmax. Kinetic studies of glutathione transferase activities in which nafenopin was mixed with normal rat liver cytosols in the assay system revealed competitive type inhibition toward 1-chloro-2,4-dinitrobenzene and a noncompetitive type of inhibition toward 3,4-dichloronitrobenzene. Likewise activities of glutathione peroxidases toward H2O2 and cumene hydroperoxide were suppressed by in vitro addition. Thus the effects of nafenopin and phenobarbital on liver biochemistry were very different. The inhibition of hepatic biotransformation and scavenger systems by nafenopin is suggested to be relevant to its hepatocarcinogenicity.
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PMID:Effects of the hepatocarcinogen nafenopin, a peroxisome proliferator, on the activities of rat liver glutathione-requiring enzymes and catalase in comparison to the action of phenobarbital. 286 89

Ferric nitrilotriacetate, which causes in vivo organ injury, induced lipid peroxidation and cell death in Ehrlich ascites tumor cells in vitro. The process was inhibited by butylated hydroxyanisole and enhanced by vitamin C and linolenic acid, indicating a close relationship between cytotoxicity and the lipid peroxidizing ability of Fe3+ NTA. The cytotoxicity was suppressed by glucose and a temperature below 20 degrees C. Lipid peroxidation of Fe3+ NTA-treated cells was greater at 0 degree C than at 37 degrees C, contrary to results with Fe3+ NTA-treated plasma membranes of Ehrlich ascites tumor cell. These results suggested that metabolism and membrane fluidity are important factors in the expression of the Fe3+ NTA-induced cytotoxicity. H2O2 showed a lower cytotoxicity than did Fe3+ NTA but a greater lipid peroxidizing ability. H2O2 appeared to damage the cells less, and was quenched rapidly by cellular metabolism unlike Fe3+ NTA. In transferrin-free medium, Ehrlich ascites tumor cell readily incorporated Fe3+ NTA, and iron uptake was greater than NTA-uptake in Fe3+ NTA-treated cells, suggesting that Ehrlich ascites tumor cell incorporated iron from Fe3+NTA and metabolized it into an inert form such as ferritin.
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PMID:Lipid peroxidation and cytotoxicity of Ehrlich ascites tumor cells by ferric nitrilotriacetate. 287 31

Treatment of three murine tumor cell lines, L929, P388, and Pan-02, in vitro with recombinant human tumor necrosis factor (rhTNF) produced evidence of oxidative damage as measured by (a) increases in intracellular glutathione levels, (b) the formation of intracellular oxidized glutathione and (c) the formation of thymine glycols in DNA. L929, the most sensitive of the three cell lines to the cytotoxic activity of rhTNF, had the lowest total glutathione content and was observed to have the highest levels of oxidized glutathione and thymine glycol formation. In addition, the radical buffering capacity of these cells was significantly compromised within 7 h of treatment with rhTNF. The P388 and Pan-02 cell lines, with total glutathione levels about 50-fold higher than L929, also showed evidence of oxidative attack, although to a lesser extent than L929. The radical buffering capacity of these cell lines was not altered by rhTNF treatment. A rhTNF-resistant subline of L929 (L929r), produced by successive passaging in vitro in the presence of TNF, increased its glutathione and oxidized glutathione levels in response to a subsequent rhTNF challenge. Meth A, a cell line resistant to rhTNF in vitro but not in vivo, showed no evidence of oxidative damage following rhTNF treatment, despite having a low radical scavenging capacity and a sensitivity to H2O2. The results with Meth A suggest that the interaction of rhTNF with this cell line does not occur in the same manner as the other cell lines, perhaps due to receptor differences or to some type of "uncoupling" of the signal-response network between the TNF receptor and a putative secondary messenger(s). These results are consistent with the hypothesis that: (a) the mechanism of action of rhTNF involves the production of oxidative damage, including damage to the DNA; (b) the sensitivity to rhTNF in vitro is related to the radical scavenging capacity of the cell; and (c) cells can respond to rhTNF challenge by increasing their free radical scavenging capacity.
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PMID:Oxidative damage in murine tumor cells treated in vitro by recombinant human tumor necrosis factor. 292 12

H2O2, in concentrations achieved in the proximity of stimulated leukocytes, induces injury and lysis of target cells. This may be an important aspect of inflammatory injury of tissues. Cell lysis in two target cells, the murine macrophage-like tumor cell line P388D1 and human peripheral lymphocytes, was found to be associated with activation of poly(ADP-ribose) polymerase (EC 2.4.2.30), a nuclear enzyme. This enzyme is activated under various conditions of DNA damage. Poly(ADP-ribose) polymerase utilizes nicotinamide adenine dinucleotide (NAD) as substrate and has been previously shown to consume NAD during exposure of cells to oxidants that was associated with inhibition of glycolysis, a decrease in cellular ATP, and cell death. In the current studies, inhibition of poly(ADP-ribose) polymerase by 3-aminobenzamide, nicotinamide, or theophylline in cells exposed to lethal concentrations of H2O2 prevented the sequence of events that eventually led to cell lysis--i.e., the decrease in NAD, followed by depletion of ATP, influx of extracellular Ca2+, actin polymerization and, finally, cell death. DNA damage, the initial stimulus for poly(ADP-ribose) polymerase activation, occurred despite the inhibition of this enzyme. Cells exposed to oxidant in the presence of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide failed to demonstrate repair of DNA strand breaks.
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PMID:Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. 294 60

Tumorilytic human blood monocytes recognize and destroy neoplastic cells by a mechanism that is nonphagocytic and requires cell-to-cell contact. The mechanism of cytolysis subsequent to binding is controversial. Release of reactive oxygen intermediates by activated rodent macrophages has been suggested as an important mechanism for tumor cell lysis in some short-term cytotoxicity assays. We examined whether oxygen intermediates are also responsible for mediating the lysis of adherent human tumor cells in a long-term (72-h) tumoricidal assay. Human blood monocytes were incubated with medium, concanavalin A-stimulated lymphokine [macrophage-activating factor (MAF)], lipopolysaccharide endotoxin, or human recombinant gamma interferon for 24 h prior to the addition of [125I] iododeoxyuridine-labeled A375 melanoma cells. The following evidence indicated that monocyte-mediated tumor cell lysis was independent of superoxide anion (O2-) and H2O2 production: (a) although human blood monocytes incubated for 24 h with gamma interferon produced twice as much O2- as control or MAF-treated monocytes, gamma interferon did not activate monocyte tumoricidal activity unless combined with lipopolysaccharide endotoxin, 0.2 ng/ml or more; (b) incubating the monocytes with 10 nM phorbol myristate acetate for 0.5 h stimulated O2- production but no cytotoxicity; (c) the cytolytic activity of MAF-treated monocytes was not decreased in the presence of catalase or superoxide dismutase; and (d) finally, peripheral blood monocytes were isolated from six patients with chronic granulomatous disease, activated by MAF or lipopolysaccharide endotoxin, and then assayed for tumoricidal activity. While these activated chronic granulomatous disease monocytes did not produce O2- or H2O2, tumor cell lysis was normal in all six patients. Hence, lysis of tumor cells in a 72-h assay is not dependent upon the generation of O2- and/or H2O2 and is intact in chronic granulomatous disease monocytes.
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PMID:Lysis of tumor cells by human blood monocytes by a mechanism independent of activation of the oxidative burst. 298 42

Addition of the tumor promoter phorbol myristate acetate to polymorphonuclear leukocytes results in the oxidation of the arylamine carcinogens; [14C]benzidine, N-[14C]methylaminoazobenzene and [14C]aminofluorene to reactive intermediate(s) that bind irreversibly to the leukocyte DNA. The binding was dependent on oxygen and was decreased by sulfhydryl inhibitors and phenolic antioxidants that inhibit the respiratory burst triggered by the phorbol myristate. Both the binding and the respiratory burst were increased by azide, presumably as a result of intracellular catalase inhibition. However higher concentrations of azide and cyanide prevented binding without affecting the respiratory burst indicating that myeloperoxidase is a catalyst for the binding. Granules isolated from the activated leukocytes and H2O2 catalyzed a cyanide sensitive benzidine binding to calf thymus DNA. Myeloperoxidase and H2O2 also catalysed extensive binding of these arylamines to calf thymus DNA. The leukocytes appear to be a useful model cell for studying one electron oxidation-catalyzed carcinogen activation.
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PMID:Peroxidase-mediated irreversible binding of arylamine carcinogens to DNA in intact polymorphonuclear leukocytes activated by a tumor promoter. 298 60

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a stimulator of chemiluminescence (CL) in SENCAR mouse epidermal cells. The CL response is TPA dose dependent (8 to 800 nM) as well as proportional to the number of cells used. Treatment with 166 nM TPA results in a CL response that peaks by 15 min although a strong response persists for over 30 min. The CL response can be inhibited by superoxide dismutase and the superoxide dismutase mimetic copper(II) (3,4 diisopropylsalicylic acid)2, suggesting that the CL response may be due to or mediated by superoxide anions. Catalase, which is specific for H2O2, and mannitol, which is a scavenger for hydroxyl radicals, had negligible inhibitory effects. The CL response is also inhibited by retinoic acid and the analogue ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8- nonatetraenoate. A series of phorbol esters with different promoting abilities produced corresponding CL responses. The second stage tumor promoter mezerein is as effective as TPA in stimulating CL. Inhibitors of various parts of the arachidonic acid cascade were found to affect the TPA-induced CL response in a manner that corresponds to their effects in vivo tumor promotion experiments: agents which are predominantly lipoxygenase inhibitors, i.e., nordihydroguaiaretic acid, benoxaprofen, or agents which are effective against both lipoxygenase or cyclooxygenase, i.e., 5,8,11,14-eicosatetraynoic acid and phenidone, are effective in diminishing the CL response. Cyclooxygenase inhibitors, i.e., indomethacin and flurbiprofen, have no or a slight enhancing effect at low doses. These data suggest that at least a major part of the TPA-induced CL response is due to the metabolism of arachidonic acid, most probably by the lipoxygenase(s). This CL assay may provide a useful system for studying the involvement of oxidants in tumor promotion.
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PMID:Suppression of tumor promoter-induced chemiluminescence in mouse epidermal cells by several inhibitors of arachidonic acid metabolism. 298 61

Polymorphonuclear leukocytes (PMN) of mice can destroy tumor cells effectively in vitro in the presence of antitumor polysaccharide, linear beta-1, 3-D-glucan from Alcaligenes faecalis var. myxogenes IFO 13140 (TAK), and some other immunomodulators. In the present study, we investigated the mechanism of the tumoricidal activity of PMN induced by these immunomodulators and especially TAK. The TAK-induced PMN cytotoxicity was concluded to involve hydrogen peroxide from the following results: (a) the cytotoxicity depended on glucose consumption; (b) it was almost completely inhibited by catalase but not affected by superoxide dismutase; (c) it was not reduced by cyanide or azide, which are inhibitors of myeloperoxidase; (d) it was not affected by scavengers of singlet oxygen or hydroxyl radical; (e) release of hydrogen peroxide from PMN was observed by the addition of TAK; (f) MM46 target cells were lysed directly by hydrogen peroxide in the absence of myeloperoxidase; (g) the supernatant of PMN in the presence of TAK, tested as a stable cytotoxic factor, did not have cytotoxic activity, and protease inhibitors had no effect on this cytotoxicity. These results suggest that hydrogen peroxide is a direct cytotoxic mediator in TAK-induced PMN cytotoxicity. Next, the mechanism of PMN cytotoxicities induced by other immunomodulators was also examined and was compared with that induced by TAK. The results suggest that hydrogen peroxide is also important for these cytotoxicities whereas, unlike the results with TAK, the H2O2:halide:myeloperoxidase system may partly participate in the cytotoxicities with some immunomodulators.
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PMID:Hydrogen peroxide as a tumoricidal mediator of murine polymorphonuclear leukocytes induced by a linear beta-1,3-D-glucan and some other immunomodulators. 299 Jun 72

6-Hydroxydopamine(6-OHDA), a specific neurotoxin against sympathetic nerve cells, is a drug already used for purging of bone marrow from neuroblastoma cells before autologous bone marrow transplantation. However, we could not detect significant differences in the toxicity of 6-OHDA against neuroblastoma and other tumor cells under the purging conditions clinically used. In contrast, bone marrow stem cells were much more resistant. The unspecific toxic effect of 6-OHDA is caused by H2O2 or H2O2-derived products which are generated by auto-oxidation in the incubation medium before a significant amount of 6-OHDA is taken up by the cells. Withdrawal of oxygen during the incubation period and subsequent incubation with an oxygen containing medium led to a more specific destruction of neuroblastoma cells which can take up 6-OHDA selectively.
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PMID:The role of reactive oxygen compounds derived from 6-hydroxydopamine for bone marrow purging from neuroblastoma cells. 299 60

It has been previously shown that skin biopsies isolated from various xeroderma pigmentosum (XP) patients present a permanent decline in catalase activity from the onset of the disease to the tumor formation. We report here that cultured XP cell strains are also markedly deficient in the catalase activity with about only 25% of the activity measured in normal human cells. No direct correlation between catalatic activity and excision repair ability has been found, since a XP variant line is as deficient as an XP-C strain. The exact cause of the catalase deficiency is still unknown but could be due to the synthesis of a modified enzyme or to an abnormal regulation leading to a limited enzyme synthesis. Furthermore, simian virus 40 transformation of normal and radiosensitive cells (XP, ataxia telangiectasia) provokes a decrease in catalase activity of about 80% compared to the control derivatives. Mathematical analysis performed on our data shows a clearcut distinction between XP and normal cells while some of the XP heterozygote cells exhibit an intermediate behavior. Although most of the XP syndrome could be explained by the impairment in the excision repair ability, the decrease in catalase activity leading to a probable increase in intracellular H2O2 concentration and/or to a higher sensitivity to any oxygen-activated species could represent an additive effect in inducing the carcinogenic process.
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PMID:Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts. 300 May 76


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