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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken to investigate the hypothesis linking peroxisome proliferation with the production of reactive oxygen species and subsequent DNA damage. Hepatic peroxisomal proliferation was induced in male Wistar-derived rats by the administration of clofibrate, methyl clofenapate, di(2-ethylhexyl)phthalate, or its metabolite mono (2-ethylhexyl)phthalate (MEHP) for periods of up to 28 days. Genotoxicity was monitored using an alkaline elution technique to assay for DNA strandbreaks and cytotoxicity was monitored by measuring lipid peroxidation. Both parameters might be expected to be elevated if peroxisome proliferation is accompanied by an elevated level of oxygen free radicals within the cell. Enzyme measurements made on the livers of the treated rats showed that peroxisomal palmitoyl CoA oxidase activity was markedly increased over control whereas peroxisomal catalase activity was not. In addition, both the cytosolic glutathione peroxidase and superoxide dismutase activities were found to be lowered in the treated animals by up to 50 and 20% respectively. Despite such changes in enzyme activity, no evidence for increases in DNA strandbreaks or lipid peroxidation was obtained with any of the chemicals at any of the time points examined. DNA strandbreaks were also assayed on hepatocytes treated in culture with MEHP (0.5 mM) for 3 days and then exposed to inhibitors of DNA repair for 2 h immediately before assay. Again, no significant increase over controls was observed. Our data suggest that any increase in radical production in the livers of rats exposed to peroxisome proliferators is not large enough to give rise to a biologically significant degree of DNA damage and that the mechanism whereby such chemicals produce liver tumours in certain rodent species may be one other than simply DNA damage due to increased production of radical species.
Carcinogenesis 1987 Sep
PMID:Lack of DNA damage or lipid peroxidation measured in vivo in the rat liver following treatment with peroxisomal proliferators. 362 60

Inhibition of colony formation by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) over a wide range of concentrations (10(-4)-10(2) ng/ml) was examined in two normal human diploid fibroblast strains and eight cell lines derived from various human tumors. Three dose-response patterns were observed: (i) no killing at any dose, which is characteristic of rodent cells; (ii) increasing cytotoxicity with TPA doses of 0.1 ng/ml or greater; and (iii) a biphasic response with maximal cytotoxicity at 1.0 ng/ml, and minimal effects at much lower or higher concentrations. The latter response group included both normal and tumor cell strains. When normal cells were incubated concurrently with superoxide dismutase or CuDIPS, survival was enhanced in a dose-dependent manner. Specific binding of [3H]PDBu to cells from each of the three response categories was studied to determine whether the cells might contain two classes of specific phorbol ester receptors. Scatchard plots yielded straight lines, consistent with one class of binding sites. The possible significance of this cytotoxic effect of TPA in human cells at dose levels usually considered typical for specific phorbol ester responses is discussed.
Carcinogenesis 1985 Dec
PMID:Differing patterns of cytotoxicity of the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in various human cell strains. 386 65

Incubation of human leukocytes with the synthetic estrogen and known human carcinogen, diethylstilbestrol (DES), for 40 min caused extensive DNA strand breakage (clastogenesis), as measured by a fluorometric assay. The level of DNA clastogenesis was dose dependent above an apparent threshold of 10 microM. Clastogenesis was increased by addition of cysteamine, a reducing agent and hydroxyl radical scavenger, and was blocked by low concentrations of plasma. DES epoxide, a weakly estrogenic derivative, was about one-tenth as potent as a DNA clastogen. Unexpected and paradoxical findings were observed when cells were treated with DES in the presence of a hydrogen peroxide-generating system plus a peroxidase. At the subthreshold concentration of 10 microM DES, the oxidizing system increased DNA clastogenicity, yet at 30 microM DES the oxidizing system decreased clastogenicity. The addition of superoxide dismutase to the oxidizing system increased clastogenicity at both concentrations of DES. DNA damage was largely blocked by arsenite, N-ethylmaleimide, iodoacetamide and bromophenacyl bromide. These experiments provide further indication of the complex nature of reactions involving DES which can lead to DNA damage and which may be relevant to DES-induced carcinogenesis.
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PMID:DNA clastogenic activity of diethylstilbestrol. 387 97

The effects of a selective detoxifier of the proximate oxygen radical, superoxide anion, on the induction of tumors in the skin of CD-1 mice by either the initiation-promotion regimen or the complete carcinogenesis process were investigated. The principle agent of interest, copper (II) (3,5-diisopropylsalicylate)2 (CuDIPS), is a low molecular weight, lipophilic copper coordination complex that catalytically disproportionates superoxide anion at a rate comparable to native Cu-Zn superoxide dismutase (SOD). The protocols used to elicit tumors were: (i) a single application of 0.2 mumol of 7,12-dimethylbenz[a]anthracene (DMBA) followed by twice-weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) in an initiation-promotion study, and (ii) either a single application of 3.6 mumol DMBA followed by no further treatment or weekly applications of 0.2 mumol DMBA in complete carcinogenesis protocols. Application of 2 mumol CuDIPS 15 min prior to the initiating dose of DMBA was without significant effect on tumor yield or incidence, whereas application prior to each dose of TPA substantially reduced tumor incidence and yield. This anti-promoting property of CuDIPS can be attributed to its SOD-mimetic activity in as much as the corresponding zinc coordination complex lacking in SOD activity, zinc (II) (3,5-diisopropylsalicylate)2, was non-inhibitory. Significant reductions in tumor yield were also observed when CuDIPS was applied prior to DMBA in either of the complete carcinogenesis protocols. Additionally, covalent binding of [3H]DMBA to epidermal DNA was markedly reduced by CuDIPS pre-treatment, suggesting that the anti-carcinogenic properties may reflect a perturbation in superoxide anion-dependent metabolic activation of DMBA. The induction by DMBA of ornithine decarboxylase activity, a biochemical marker of tumor promoter activity, was not affected by CuDIPS; however, induction of ornithine decarboxylase by TPA was potently blocked. Collectively, these effects of a biomimetic SOD further implicate reactive oxygen species at multiple stages in chemical carcinogenesis.
Carcinogenesis 1985 Aug
PMID:Effects of a biomimetic superoxide dismutase on complete and multistage carcinogenesis in mouse skin. 392 37

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

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

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) influences neither the State 3 nor the State 4 respiration in rat liver mitochondria. The respiratory control and ADP/O ratio were also unaffected by TPA. The oligomycin-sensitive ATPase activity in submitochondrial particles remained unaltered upon TPA addition, whereas the NADH oxidase activity was slightly inhibited at a very high concentration of TPA (15% decrease at 17 microM TPA). The activity of the superoxide dismutase located to the mitochondria was insensitive to the tumor promoter, and no change in the rate of H2O2 production was found on TPA treatment in vitro. Thus, the mitochondrion is not a likely candidate for the site of action of the tumor promoter.
Carcinogenesis 1983
PMID:Oxygen uptake, ATPase activity, and superoxide dismutase activity in isolated rat liver mitochondria are not influenced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 622 26

The effect of the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) on superoxide (O-.2) production and superoxide dismutase (SOD) levels has been investigated in human leukocytes and human and rodent fibroblast cell lines. Both O-.2 production and a lowering of the SOD levels were observed in the human leukocytes, but these changes could not be correlated with the induction of gross chromosomal aberrations by TPA. Similarly the use of an O-.2-generating system failed to induce chromosome aberrations. However, a small percentage increase in chromosome aberrations was observed in human fibroblasts after repeated and prolonged exposure to TPA. TPA was shown to reduce the SOD levels in these cells. Overall however, the data suggest that the chromosomes are not the primary site of action for the superoxide anions produced by TPA.
Carcinogenesis 1983
PMID:Investigation of a possible role for superoxide anion production in tumour promotion. 630 27

Autoxidation of active metabolites of naphthylamine and aminoazo dyes in neutral buffer generated hydrogen peroxide (H2O2) and superoxide anion (O-.2), as detected by the titanium sulfate method and nitro blue tetrazolium method, respectively. 2-Amino-1-naphthol, 1-amino-2-naphthol, 1-amino-4-naphthol, N-hydroxy-2-aminonaphthalene, N-hydroxy-1-aminonaphthalene, N-hydroxy-4-aminoazobenzene and N-hydroxy-4-methylaminoazobenzene generated H2O2 and O-.2, whereas 1-nitrosonaphthalene, 2-nitrosonaphthalene, 1-naphtylamine, 2-naphthylamine and non-carcinogenic aminonaphthols and naphthols generated no active oxygens. Catalase and superoxide dismutase were used to identify the formation of these active oxygens. For all compounds tested except nitrosonaphthalenes, good parallelism was found between the active oxygen formation and convertibility to free radicals. These results suggest a possible role of free radicals and subsequently formed active oxygens in aromatic amine carcinogenesis.
Carcinogenesis 1983
PMID:Generation of hydrogen peroxide and superoxide anion from active metabolites of naphthylamines and aminoazo dyes: its possible role in carcinogenesis. 630 28


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