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)

The hypothesis that hepatocarcinogenesis resulting from treatment of rats and mice with peroxisome proliferators is linked to increased cellular levels of hydrogen peroxide from peroxisomal beta-oxidation was investigated. Male F344 rats and female B6C3F1 mice were treated for 14 days with di(2-ethylhexyl)phthalate (DEHP) or di(2-ethylhexyl)adipate (DEHA), industrial plasticizers, or nafenopin, a hypolipidemic drug. Activities of enzymes responsible for the production [peroxisomal palmitoyl CoA oxidase (PCO)] and degradation [catalase (Cat) and glutathione peroxidase (GSHPx)] of H2O2 were assayed in liver homogenates prepared from treated animals. The activities of the peroxisomal enzymes PCO and Cat were enhanced 5- to 25-fold and 1.5- to 3-fold respectively by treatment with the peroxisome proliferators. The activity of GSHPx, a cytoplasmic enzyme, was decreased 40-60% in liver homogenates prepared from treated animals compared to control animals. A kinetic treatment of the rates of formation of hydrogen peroxide by PCO, and of degradation of hydrogen peroxide by catalase was used to estimate steady-state hydrogen peroxide concentrations ([H2O2]) during peroxisomal oxidation of palmitoyl CoA. Increases in peroxisomal steady-state [H2O2] for the F344 rat liver homogenates correlated well with the carcinogenic potential of these chemicals, determined in previous carcinogenicity studies. Increases in the steady-state [H2O2] were also calculated for liver homogenates prepared from mice treated with these compounds. Decreases in liver lipid peroxidation were observed after treatment with each chemical in both species. The results of these studies are consistent with an involvement of increased peroxisomal hydrogen peroxide in the hepatocarcinogenesis of these compounds.
Carcinogenesis 1986 Nov
PMID:In vitro steady-state levels of hydrogen peroxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators. 376 36

The tumor promoter phorbol-12-myristate-13-acetate (PMA) increases the level of poly ADP-ribosylation of chromosomal proteins in mouse embryo fibroblasts C3H10T1/2. The poly ADP-ribosylated nuclear proteins fall into the following molecular weight classes: 40, 48, 61, 77, 92, 158, 200 kd. Preincubation with catalase reduced the poly ADP-ribose (ADPR) substitution of all these proteins essentially to control levels. Western blot analysis with antibody directed against ADPR transferase indicates that the major acceptors are ADP-ribose transferase (116 kd) itself and its proteolytic degradation products of 20-25, 45 and 72-95 kd. Poly ADP-ribosylation of these proteins is suppressed by cycloheximide, 3-aminobenzamide, antipain and catalase. The latter three inhibitors possess anti-promotional activities in certain in vitro cell culture systems. Auto-poly ADP-ribosylation of ADPR transferase and its proteolytic cleavage as well as the poly ADP-ribosylation of other chromosomal proteins may play a role in the modulation of gene expression by PMA.
Carcinogenesis 1985 Oct
PMID:Non-histone chromosomal protein acceptors for poly(ADP)-ribose in phorbol-12-myristate-13-acetate treated mouse embryo fibroblasts (C3H10T1/2). 393 85

After application of tetradecanoylphorbol acetate to mouse skin, a decrease in the specific activity of catalase in epidermal extracts has been observed, confirming the observation of earlier workers. However, this decrease in specific activity is largely due to an increase in extractable protein and not an actual decrease in catalase activity per animal skin. Thus changes in specific activity of components in epidermal extracts need to be interpreted with caution.
Carcinogenesis 1986 Mar
PMID:Measurement of enzyme activities in mouse epidermis following phorbol ester treatment: a potential artifact. 394 33

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

In order to gain an insight into the nature of the radiomimetic activity by which the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) alters cell cycle parameters in HeLa cells, possibilities of modifying the TPA-induced G2 block and recovery from it were studied. TPA-induced G2 blockage was analysed by counting mitotic figures. It was not influenced by hydroxyurea (10(-3) M) thus indicating that it is independent of DNA synthesis. TPA-induced decrease of mitotic activity occurred faster than that caused by cycloheximide (10(-5) M) indicating that the TPA-sensitive transition point in G2 is closer to mitosis than that for cycloheximide. Superoxide dismutase, catalase, alpha-tocopherol, the radioprotector S-(2-aminoethyl)isothiuroniumbromide.HBr (AET), caffeine and indomethacin and eicosatetraynoic acid (ETYA), both inhibitors of oxygenases in the arachidonic acid cascade, were not capable of reducing the TPA-induced G2 response. Under certain conditions small concentrations of AET (10(-8) M) and ETYA (10(-8) M) appeared to improve recovery slightly. Mannitol and sorbitol, however, both hydroxyl radical scavengers at 0.1 M concentration reduced TPA-effectiveness to a large degree (0.1 M D- and L-mannose were ineffective). Dimethylsulfoxide (0.1 M), another hydroxyl radical scavenger, was ineffective.
Carcinogenesis 1985 Sep
PMID:Mechanistic aspects of the delay in the G2 phase of the cell cycle caused by tumor promoter 12-O-tetradecanoylphorbol-13-acetate in HeLa cells. 402 35

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

In conclusion, the aniridia and the retinoblastoma stories tell us the importance of applying high-resolution cytogenetic techniques and of measuring catalase and esterase D activities when screening and investigating patients and their families. They also point to exceptional situations in carcinogenesis, and without doubt the newly devised genetic techniques, such as recombinant DNA, will allow, when applied to these conditions, a far better understanding of carcinogenesis at the molecular level--which is the important one.
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PMID:Toward clinical microcytogenetics: the aniridia and the retinoblastoma stories. 629 11

There is much evidence from in vivo and in vitro carcinogenesis studies that active oxygen species play a role in tumor promotion. We tested directly whether superoxide produced extracellularly by xanthine-xanthine oxidase (X-XO) has the capacity to promote initiated mouse embryo C3H/10T1/2 fibroblasts. Cell cultures initiated with either 137Cs gamma-rays or benzo[a]pyrene diol epoxide I were found to transform 3-30 times more effectively when subsequently treated daily for 3 weeks with nontoxic doses of X-XO. Scavengers of active oxygen radicals such as superoxide dismutase or superoxide dismutase in combination with catalase reduced the frequency of appearance of transformed foci by 3-25 times when compared to cultures receiving X-XO alone. These results show that active oxygen species such as superoxide and H2O2 can act in a promotional manner that mimics the effects of the mouse skin promoter phorbol 12-myristate 13-acetate in this system. X-XO also acted as a weak complete carcinogen.
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PMID:Active oxygen acts as a promoter of transformation in mouse embryo C3H/10T1/2/C18 fibroblasts. 642 26

We have studied the effects of superoxide dismutase (SOD), catalase, Cu(II) (3,5-diisopropylsalicylate)2 (CuDIPS) and other copper compounds on radiation transformation in vitro using C3H 10T1/2 cells. When present only during irradiation, high concentrations of SOD in the medium enhanced transformation, while catalase, inactivated SOD (autoclaved), CuDIPS, cupric chloride and cuprous chloride inhibited the initiation phase of radiation transformation. SOD, catalase and CuDIPS did not affect the expression phase of radiation transformation. Suppression of the TPA enhancement of transformation by catalase was a highly significant effect, while the suppression by SOD was not of statistical significance. Our results suggest that hydrogen peroxide (H2O2) may be important in the cellular damage leading to malignant transformation.
Carcinogenesis 1984 Oct
PMID:Role of free radicals in the initiation and promotion of radiation transformation in vitro. 648 46

The mechanism of action of tumor promoters may involve the modulation of gene expression, e.g., the induction of ornithine decarboxylase (ODC). The tumor promoter phorbol-13-myristate-12-acetate (PMA) induces chromosomal damage via the intermediacy of active oxygen species which may trigger the activation of certain genes. Therefore, we have studied the effect of antioxidants on the induction of ODC by PMA, medium change only and medium change plus PMA in mouse mammary tumor cells Mm5mt/C1. CuZn-superoxide dismutase (SOD, a scavenger of superoxide radicals), catalase (CAT, a scavenger of hydrogen peroxide) and mannitol (a scavenger of hydroxyl radicals) suppressed ODC induction under all three conditions. The relative inhibitory potency of the antioxidants was always SOD less than CAT less than mannitol less than SOD + CAT. Maximal suppression by SOD + CAT was approximately 50%. It is concluded that active oxygen species play a role in ODC induction by factors contained in serum and by PMA.
Carcinogenesis 1983 Nov
PMID:The induction of ornithine decarboxylase by phorbol 12-myristate 13-acetate or by serum is inhibited by antioxidants. 664 Aug 44


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