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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

Selenium, glutathione peroxidase, glutathione reductase and glyoxalase I have been measured in normal and neoplastic human adult lung tissues. Interindividual variations of enzyme activities and selenium content in both tumour and non-tumour tissues were considerable. From the measurements of glutathione peroxidase activity with both hydrogen peroxide and cumene hydroperoxide it was deduced that human tumour and non-tumour lung tissues are devoid of the selenium-independent enzyme. In general, a significant increase in the activity of glutathione peroxidase and glutathione reductase was found in tumour. Glyoxalase I in tumour was as high as in non-tumour samples. Mean selenium concentration tended to be higher in tumour than in non-tumour specimens. When a comparison was made between normal and neoplastic tissue of the same individual, glutathione peroxidase, activity was found to be higher in tumour in 19 cases out of 24 and glutathione reductase in 17 out of 22. In 15 cases out of 18 the selenium levels were found to be higher in tumour. It was concluded that changes in the factors involved in anti-oxidative protection actually occur in human lung tumour tissues.
Carcinogenesis 1987 Feb
PMID:Selenium level and glutathione-dependent enzyme activities in normal and neoplastic human lung tissues. 380 12

The effect of dietary selenium levels on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors was examined in mice fed a semi-purified diet (20% casein, 50% sucrose, 5% corn oil). (C57BLxDBA/2f)F1 (BD2F1) female mice were fed diets containing 0.2, 0.5, 1.0 and 2.0 p.p.m. selenium starting at 7 weeks of age. The mammary tumor incidence was 56, 30, 25 and 16%, respectively, after the mice were on the diet for 9 months. In a second experiment, BALB/cV female mice were fed diets containing 0.2 and 2.0 p.p.m. selenium. After 9 months on the diet, the mammary tumor incidence was 39 and 7%, respectively. Both strains of mice grew equally well on the 0.2 and 2.0 p.p.m. selenium diets indicating that the highest dietary selenium level was compatible with normal growth. The selenium concentration and selenium dependent-glutathione peroxidase (GSH-Px) activity of mammary glands from control BD2F1 mice fed 0.2, 1.0 and 2.0 p.p.m. dietary selenium was examined at 8, 9 and 10 months of age. As in previous experiments in adult BALB/c mice, the concentration of mammary gland selenium, but not GSH-Px activity, increased with increasing levels of dietary selenium. These results document that nutritional levels of dietary selenium (0.5 p.p.m. Se) as well as non-toxic higher levels (2.0 p.p.m. Se) inhibit DMBA-induced mammary tumorigenesis.
Carcinogenesis 1983 Sep
PMID:Effect of dietary selenium levels on 7,12-dimethylbenzanthracene-induced mouse mammary tumorigenesis. 641 77

The mixed-function oxidase system shows a number of variations in the liver of diethyl-nitrosamine (DEN) treated rats. These include a decrease of the cytochrome P450 content and of the aminopyrine demethylase activity both in the hyperplastic nodules and in the hepatoma. Processes of detoxification, such as the glutathione system, show some modifications. These alterations are in accordance with the decrease of glutathione peroxidase and the increase of gamma-glutamyltranspeptidase during diethyl-nitrosamine carcinogenesis.
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PMID:Functional alterations of the endoplasmic reticulum and the detoxification systems during diethyl-nitrosamine carcinogenesis in rat liver. 647 42

A clinical study was undertaken to determine whether oral contraceptives (OCs) affect the activity of the enzyme glutathione peroxidase. OC users recruited for the study were volunteers attending the Redhill Family Planning Clinic in England. Their demographic characteristics were noted. Pre- and postmenopausal comparative subjects were also used. The laboratory procedures involved in the study are described. Findings are tabulated. The average erythrocyte glutathione peroxidase levels of women using OCs for more than 7 months were significantly higher than those of the pre- and postmenopausal subjects. These levels increased progressively with duration of OC use. These levels did not fluctuate with the menstrual cycle in either OC or non-OC users. Levels of erythrocyte selenium and plasma pyridoxal were not significantly altered by OC use. Riboflavin status, however, as estimated by glutathione reductase activity was substantially lower in OC users and was lowest in women who had used OCs for the longest amount of time. Riboflavin status was found to be directly correlated with erythrocyte glutathione peroxidase levels. These findings may be important because selenium is currently believed to offer protective benefits against carcinogenesis, especially breast cancer. All the OCs studied produced the same effects.
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PMID:The effect of prolonged oral contraceptive steroid use on erythrocyte glutathione peroxidase activity. 679 91

Selenium ingestion may inhibit carcinogenesis. Epidemiologic studies have shown that age-adjusted death rates for cancer at most head and neck sites are lower in states where the soil and forage crops contain higher levels of selenium. The mode of action is incompletely understood, but may be mediated through an increase in the activity of the selenium dependent, antioxidant enzyme glutathione peroxidase (GSH-Px). The authors studied blood selenium levels and blood and tissue GSH-Px activities in 50 patients with untreated cancer of the oral cavity and oropharynx. Mean erythrocyte selenium and glutathione peroxidase were significantly depressed when compared to age-matched controls. Mean plasma selenium, on the other hand, was significantly elevated in the cancer patient group. Data from subsets within the cancer patient group were also discussed. GSH-Px activity did not differ in tumor and adjacent normal tissue. The concept of chemoprevention of carcinogenesis with inhibitory chemical compounds is particularly apropos to head and neck cancer control. Further work is indicated to determine if ingestion of supplemental selenium corrects the abnormalities identified here, and what affect, if any, this would have on the development and behavior of squamous cell cancers in the upper aerodigestive tract.
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PMID:Selenium and glutathione peroxidase levels in patients with epidermoid carcinoma of the oral cavity and oropharynx. 682 99

The biochemical and clinical effects of selenium (Na2SeO3) on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Sprague-Dawley rats are presented. A 4-ppm selenium supplement to the drinking water was provided before, during, and after 20 weekly injections of 20 mg DMH per kg body weight. Immediately after the 20th DMH injection, part of the rats were sacrificed. The incidences of colon tumors in groups provided selenium before DMH, before and during DMH, and only during DMH treatment were reduced to 39, 43, and 36%, respectively. The incidence in the DMH only control was 63%. Other rats in all treated and control groups were maintained up to 5 months post-DMH treatment. At 10-week intervals throughout the study, selected blood and tissue components were analyzed. The following hematological changes correlated with DMH treatment. (a) Serum glutamic oxalacetic transaminase increased 2-fold (normal, 66 +/- 14 g/dl). (b) Serum alkaline phosphatase increased 24% (normal, 166 +/- 56 units/liter). (c) Serum protein decreased 14% (normal, 6.77 +/- 0.48 g/dl). (d) White blood count increased 2- to 3-fold (normal, 7.7 +/- 2.7 X 10(3)/cu mm). And (e) hemoglobin decreased 67% (normal, 18.1 +/- 1.3 g/dl). The magnitude of these changes varies with each selenium treatment group and with each 10-week analysis period. Provision of 4 ppm selenium doubled both liver and blood selenium levels compared to unsupplemented controls. The effects of selenium and DMH treatments on glutathione peroxidase and beta-glucuronidase activities and on sialic acid are presented. Possible mechanisms by which selenium protects against DMH-induced neoplasia are discussed.
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PMID:Biochemical and clinical effects of selenium on dimethylhydrazine-induced colon cancer in rats. 730 70

In this report the effects of single doses of ionizing radiation on the mRNA expression of several proteins involved in multiple drug resistance were analyzed. Murine NIH 3T3 cells treated with single doses of 5, 10 and 20 Gy during the time interval from 1.5 to 72 h after irradiation were compared with their corresponding controls at the same points of time. The glutathione S-transferase-pi (GST pi) level was elevated in cells treated with 10 or 20 Gy from 24 to 72 h after irradiation compared with the control. Topoisomerase II alpha and thymidylate synthase were decreased in irradiated cells 24-72 h after exposure. These down-regulations were associated with cellular proliferation, determined by mRNA expression of the proliferation marker histone 3. Irradiated cells exhibited no alteration in the P-glycoprotein or glutathione peroxidase mRNA content. The finding that GST pi mRNA was overexpressed after irradiation was validated by investigations on a human lung carcinoma cell line (LXF 289) on the mRNA and protein level. Thus, our results indicate that irradiation alters the expression of proteins involved in multidrug resistance and may, therefore, play a role in clinical drug response.
Carcinogenesis 1995 Sep
PMID:Effects of single doses of irradiation on the expression of resistance-related proteins in murine NIH 3T3 and human lung carcinoma cells. 755 53

Hyperplastic nodular cirrhosis was induced in rats by long-term (6 month) i.p. administration of thioacetamide at doses of 2.66 mmol/kg body wt, three times per week. The survival rate of animals at the end of the treatment was 90%. To follow the temporal changes samples at 0, 7, 15, 30, 45, 60, 90, 150 and 180 days from rats during thioacetamide intoxication and from chronological controls were obtained. The cirrhogenic ability of this treatment was assessed on the basis of morphological changes: the development of macronodular cirrhosis and the appearance of fibrous septa of collagen through portal spaces. Parameters of liver injury and cholestasis were obtained by assaying the serum activities of isocitrate dehydrogenase and gamma-glutamyltransferase. Enzymes and metabolites related to glutathione redox systems, as well as other antioxidant enzymes, were tested. Catalase and glutathione peroxidase, the two enzymes involved in the elimination of peroxides, and glutathione reductase decreased significantly at the end of the 6 months of intoxication, while Cu-Zn and Mn superoxide dismutases increased progressively during the long-term thioacetamide treatment. Protein thiol levels profile showed a biphasic change increasing from the 7th day and were insensitive to the 30% depletion of intracellular glutathione (GSH). To study the relationship of the intracellular thiols on the mechanisms of cell proliferation and differentiation during the cirrhogenic process, DNA content was assayed by flow cytometry in isolated hepatocytes, and DNA ploidy and distribution between G0-G1, S and G2 + M phases were determined. Remarkable changes in relation to a sharp increase in diploid population from 7 to 180 days (24.5%-->85.5%), a pronounced decrease in polyploid populations (tetraploid+octoploid) in the same period (73.7%-->12.3%), and elevations in the populations in S phase (S1 + S2) were observed in thioacetamide-treated rats. The results obtained indicate that hepatocytes isolated from thioacetamide-treated rats showed a marked tendency to diploidy, an enhancement in DNA replication parallel to the hepatic content of protein sulphydryl groups and a significant decline in antioxidant enzyme activities. The increase in protein thiols was independent of GSH level and of the thiol redox state.
Carcinogenesis 1995 Jul
PMID:Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. 761 93

Evidence is mounting supporting a role for oxidative stress in the mechanism of tumour promotion in response to agents such as 12-O-tetradecanoylphorbol-13-acetate (TPA). In this paper we demonstrate that glutathione peroxidase-mimetic xenobiotics, ebselen, ebselen-glutathione, alpha-(phenylselenenyl) acetophenone and bis-(4-aminophenyl) telluride (at concentrations between 10 microM and 50 microM) all demonstrate protective effects on TPA-induced downregulation of gap-junctional intercellular communication (GJIC) between WB-F344 rat liver epithelial cells. These effects were, in each case, diminished if the cells were depleted of their intracellular glutathione, and potentiated if glutathione was supplemented into the incubations. Additionally, bis-(4-aminophenyl) selenide and several N-substituted analogues, possessing potent antioxidant activity but being devoid of GSH peroxidase-mimetic activity, demonstrated remedial activity against TPA-induced downregulation of GJIC. Structure-activity relationships between these molecules showed a strong correlation to the oxidation potential of the selenium atom in the compound as the bis-(4-nitrophenyl)- and bis-(4-cyanophenyl)- derivatives, which possess poor antioxidant capacity and a half-wave redox potential well above +1.0 V, did not affect TPA-induced effects on GJIC. Examination of the mechanism of action of these redox-active compounds demonstrated correlations between their abilities to (i) prevent TPA-induced downregulation of GJIC, (ii) abolish the accumulation of intracellular oxidants and (iii) prevent the hyper-phosphorylation and internalization of connexin 43 in the cells. The active compounds were also able to prevent the rapid, TPA-induced translocation of protein kinase C to the particulate fraction of the cells, without affecting phorbol ester binding. These data support a synergistic role for oxidants and other TPA-dependent responses within the cell in mediating the downregulation of GJIC. Such oxidative metabolism may play a role in the control of translocation of protein kinase C from the cytosol to membranes in response to TPA within these cells. Despite the nature of the in vitro test system studied, the data also clarify the molecular basis for a potential anti-tumour promotive effect of antioxidants, based on established redox chemistries of several series of structurally-related molecules.
Carcinogenesis 1995 Aug
PMID:Redox-active chalcogen-containing glutathione peroxidase mimetics and antioxidants inhibit tumour promoter-induced downregulation of gap junctional intercellular communication between WB-F344 liver epithelial cells. 763 9


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