Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report shows that generation of hydrogen peroxide (H2O2) by human polymorphonuclear leukocytes (PMNs) activated with tumor promoters of varying potency as first and second stage promoters correlates well with activities of these promoters in vivo. Those tested were 12-O-tetradecanoylphorbol-13-acetate (TPA), a complete promoter, 12-O-retinoylphorbol-13-acetate (RPA), a synthetic TPA derivative almost devoid of first stage activity in some strains of mice, and mezerein (Mez), a potent second stage and much weaker first stage promoter. Mez-stimulated PMNs produced up to four times less H2O2, whereas RPA-stimulated PMNs produced up to 10 times less H2O2 than TPA-activated cells when used at concentrations between 0.5 and 15 nM to activate 7.5-8.5 X 10(4) PMNs/ml. Phorbol, a non-promoter, was totally inactive in this assay. Furthermore, the tumor promoter-activated PMNs caused formation of 5-hydroxymethyl-2'-deoxyuridine (HMdU) and thymidine glycol (dTG) in DNA co-incubated with those cells. The amounts of modified thymidines formed, particularly of HMdU, correlated well with first stage tumor promoting efficacy and with the amount of H2O2 that was generated by promoter activated PMNs. In comparison with TPA, Mez- or RPA-stimulated PMNs induced formation of 25 or 70% less H2O2 and 30 or 75% less HMdU, respectively, under conditions favoring HMdU formation. Thus, formation of either H2O2 by tumor promoter-stimulated phagocytes or HMdU in DNA exposed to those activated cells may serve as a measure of potency as a first stage tumor promoter. Formation of modified bases such as HMdU in DNA might constitute the genetic change imparted by the first stage tumor promoters.
Carcinogenesis 1987 Mar
PMID:Hydrogen peroxide formation and DNA base modification by tumor promoter-activated polymorphonuclear leukocytes. 381 40

The possibility that ascorbic acid, as a nucleophile, may inhibit mutagenicity induced by electrophilic metabolites of N-nitroso compounds was examined. In vitro data are presented to show that ascorbic acid does not decrease the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a modified Ames bacterial mutagenicity system if deionized water is used to prepare the incubation medium. However, ascorbic acid prevents the mutagenicity of MNNG in vitro if added to bacteria in a medium prepared with either sterile tap water or deionized water and Cu2+ ions and that this antimutagenic response is blocked by EDTA. Additional in vitro experiments suggest that when ascorbic acid and Cu2+ ions are mixed in aqueous solution, H2O2 and free radicals derived from H2O2 are formed and these compounds may deactivate N-nitroso compounds. In vivo data are presented to show that ascorbic acid supplementation to guinea pigs (2000 mg/kg body weight/day) has no effect on the mutagenicity of N-nitrosodimethylamine, MNNG, N-methylnitrosourea and streptozotocin using the intrahepatic host-mediated bacterial mutagenicity assay. Additional in vivo studies demonstrate that simultaneous oral administration of ascorbic acid prevents the mutagenicity that follows the intragastric nitrosation of aminopyrine by nitrite while dietary pre-treatment with ascorbic acid does not. These findings suggest that ascorbic acid can block the intragastric formation of mutagenic N-nitroso compounds but that ascorbic acid has no effect on mutagenicity of N-nitroso compounds once they are formed.
Carcinogenesis 1985 Nov
PMID:Studies on the antimutagenic activity of ascorbic acid in vitro and in vivo. 393 30

3-Hydroxybenzo[a]pyrene (3-OH-BaP) is oxidized by the horseradish peroxidase/H2O2 system to benzo[a]pyrene-3,6-quinone. In the presence of N-acetylcysteine one other product is also formed. This was identified by its chemical, and u.v., mass and n.m.r. spectral properties as 6-(H-acetyl-cystein-S-yl)-3-hydroxybenzo[a]pyrene (6-NAc-cys-3-OH-BaP). Replacement of the N-acetylcysteine by glutathione leads to the formation of a 3-OH-BaP-glutathione adduct. Enzymic hydrolysis of benzo[a]pyrene-3-glucuronide in the presence of N-acetylcysteine yields, in addition to 3-OH-BaP, a product which co-chromatographs with 6-NAc-cys-3-OH-BaP and has identical chemical and spectral characteristics.
Carcinogenesis 1986 Mar
PMID:Reactive intermediates from 3-hydroxybenzo[a]pyrene and its glucuronide. 394 31

Benzidine is oxidized by the peroxidase/H2O2 system, yielding reactive intermediates. In the presence of thiols, covalent adducts are formed. We used h.p.l.c. to separate the products of the reaction of benzidine with N-acetylcysteine. The major product was identified by n.m.r. spectroscopy (1H-n.m.r.) as 3-(N-acetylcystein-S-yl)-benzidine.
Carcinogenesis 1985 Jan
PMID:Identification of the N-acetylcysteine conjugate of benzidine formed in the peroxidase activation system. 396 36

Because oxygen intermediates secreted by inflammatory leukocytes are postulated to play a role in potentiating carcinogenesis, we investigated the ability of macrophages to induce oxidative DNA damage in eukaryotic cells. Murine macrophages, obtained from sites of inflammation and stimulated with 12-O-tetradecanoylphorbol-15-acetate, induced the formation of 5,6-ring-saturated thymine bases in the DNA of cocultured NIH-3T3 cells; macrophages or 12-O-tetradecanoylphorbol-15-acetate alone did not induce such alterations. Reagent H2O2, at concentrations produced by macrophages in the ambient medium (i.e., approximately 10(-5) M), induced saturated thymines in the target cells in a dose-dependent manner. The reaction between reagent H2O2 and cellular DNA was rapid, reaching maximum levels in 30 min, and similar amounts of saturated thymines were induced at 4 degrees or 37 degrees. The 3T3 targets were able to repair the saturated thymines rapidly (i.e., over 70% of the lesion was removed in 2 hr). Catalase completely inhibited macrophage-mediated induction of saturated thymines, although superoxide dismutase enhanced induction. Taken together, the data indicate that macrophages exposed to phorbol diesters can induce a specific, quantifiable lesion in the DNA of bystander eukaryotic cells and that reactive oxygen species from the macrophages participate in producing the lesion.
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PMID:Induction of 5,6-ring-saturated thymine bases in NIH-3T3 cells by phorbol ester-stimulated macrophages: role of reactive oxygen intermediates. 397 73

The mechanisms by which tumor promoters exert their effects on target tissues are not clearly understood. Recent studies have demonstrated that phorbol ester tumor promoters induce an oxidative burst in phagocytes and DNA single-strand breaks (SSB) in leukocytes. The purpose of the research presented here was to investigate the clastogenic effects of tumor promoters in the target cell population, primary mouse epidermal cells co-incubated with leukocytes. Using the alkaline elution assay to detect DNA SSB, it was demonstrated that tumor promoters induce DNA SSB in primary mouse epidermal cells incubated in the presence of leukocytes. By increasing the ratio of leukocytes to epidermal cells from 1:2 to 10:1, in the presence of 1.6 X 10(-6) M 12-O-tetradecanoylphorbol-13-acetate (TPA), a ratio dependent increase in DNA SSB was observed (from 9 X 10(-2) to 121 DNA SSB per 10(6) nucleotides). A dose response in DNA SSB was seen with TPA over a concentration range of 4 X 10(-9)-1.6 X 10(-6) M. Mezerein, a second stage tumor promoter, induced similar levels of DNA SSB to that of TPA. 4-O-Methyl TPA, a first stage tumor promoter, induced significantly fewer DNA SSB than either TAP or mezerein at similar concentrations. The induction of DNA SSB in epidermal cells treated with TPA and co-incubated with leukocytes was inhibited by catalase but not superoxide dismutase. These data indicate that tumor promoters can act indirectly on target epidermal cells by stimulating the release of a clastogenic factor from leukocytes through a mechanism involving H2O2.
Carcinogenesis 1985 Sep
PMID:Indirect induction of a clastogenic effect in epidermal cells by a tumor promoter. 402 25

N-Hydroxy-N-2-fluorenylacetamide, a proximate carcinogenic metabolite of N-2-fluorenylacetamide, is oxidized largely to 2-nitrosofluorene by lactoperoxidase or extract of peroxidative activity of rat uterus in an H2O2- and Br- -dependent reaction. Evidence is presented that the oxidizing species includes OBr- (HOBr). This novel oxidation may be involved in carcinogenesis by N-arylhydroxamic acids.
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PMID:A novel oxidation of the carcinogen N-hydroxy-N-2-fluorenylacetamide catalyzed by peroxidase/H2O2/Br-. 403 95

Adriamycin (ADR) failed to inhibit and paradoxically enhanced the biological action of 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis in vivo and in vitro. In the presence of ADR, the tumor promoter caused a greater sequential rapid increase and prolonged decrease in glutathione (GSH) peroxidase (GSH:H2O2 oxidoreductase, EC 1.11.1.9) activity accompanied by a greater decrease in the ratio of reduced (GSH)/oxidized (GSSG) glutathione in isolated epidermal cells. The ability of ADR to deplete the intracellular level of GSH correlated with its ability to increase basal and TPA-induced ornithine decarboxylase (ODC, L-ornithine carboxylase, EC 4.1.1.17) activities. In vivo, topical ADR treatments also enhanced TPA-induced ODC activity as well as the tumor-promoting ability of TPA in the two-stage system of mouse skin carcinogenesis. Since lipid peroxidation has been associated with ADR toxicity, these data suggest that the enhancement of the tumor-promoting ability of TPA by ADR may be the result of an increased oxidative challenge that overwhelms the GSH-dependent antioxidant protective system of the epidermal cells.
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PMID:Enhancement by adriamycin of the effects of 12-O-tetradecanoylphorbol-13-acetate on mouse epidermal glutathione peroxidase activity, ornithine decarboxylase induction and skin tumor promotion. 407 83

The oxidation of NH3 to NO3- by rat liver in vitro is described. A xanthine-xanthine oxidase reaction also oxidized NH3 to NO3- when H2O2 was added. An in vivo inhibitor of superoxide dismutase enhanced the in vitro liver conversion of NH3 to NO3-. Thus, intracellular oxidation by activated oxygen likely represents the source of endogenously formed NO3- in mammals.
Carcinogenesis 1984 Sep
PMID:Activated oxygen and mammalian nitrate biosynthesis. 608 4

There is growing evidence that natural killer (NK) cells play an important role in immune surveillance against tumors and certain infections. The coexistence of activated neutrophils with lymphocytes in tumor masses and inflammatory tissues suggests the possibility of interaction between secreted neutrophil products and nearby lymphocytes. We examined the susceptibility of lymphocyte NK activity to oxidative injury by the neutrophil myeloperoxidase (MPO) system and H2O2 with the use of a cellfree model system. Exposure of human mononuclear leukocytes (MNL) to MPO, an H2O2-generating system (glucose + glucose oxidase), and a halide (C1- or I-) resulted in marked suppression of MNL-NK activity, as measured by 51Cr release from K562 tumor targets (p less than 0.001). This suppression was dependent on the presence and activity of each system component and was blocked by azide and catalase, but not by heated catalase. In spite of the marked functional suppression of NK activity, MNL viability was more than 95% and target binding frequency was not affected. NK suppression was reversible after 24 hr in culture. The mechanism of suppression was dependent on the amount and rate of H2O2 delivered, and on MNL number. MPO was essential when H2O2 flux was low or when MNL numbers were high. As H2O2 flux increased or MNL numbers decreased, NK suppression gradually became MPO-independent and was mediated by H2O2 alone. The ability of the MPO system to compromise lymphocyte NK function may explain the in vitro inhibition of NK activity of mixed cell populations by the tumor promoter phorbol esters, because these agents are potent stimulants for neutrophil secretion of MPO and H2O2. This study may also provide a possible mechanism for the reported in situ NK activity suppression by adherent phagocytic cells during carcinogenesis in both humans and animals.
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PMID:Down-regulation of human natural killer activity against tumors by the neutrophil myeloperoxidase system and hydrogen peroxide. 609 70


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