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)

Aflatoxin B1-induced hepatic gamma-glutamyl transpeptidase-positive foci were quantified in rats fed different levels of fat and selenium during either initiation or early promotion. Male Sprague-Dawley rats were divided into 12 groups. One of six experimental diets were fed to groups 1-6 prior to and during aflatoxin B1 exposure (initiation, weeks 1-4.5) and to groups 7-12 during weeks 4.5-15 (promotion). The six experimental diets contained 2 or 20% corn oil, each with either less than 0.02, 0.15 or 2.5 (or 1.9) p.p.m. selenium. When not fed the experimental diets, rats were fed a modified AIN-76A diet. In groups 1-6, 0.03% phenobarbital was added as a promoter to the AIN-76A diet. Individual and interactive effects of selenium and fat were dependent on the stage of carcinogenesis. High dietary fat fed with either less than 0.02 or 0.15 p.p.m. selenium during initiation resulted in a significant increase in the number and size of foci when compared with low fat groups. In rats fed 20% fat and 2.5 p.p.m. selenium during initiation, preneoplastic development was reduced below all low fat groups. In contrast, selenium status but not dietary fat level influenced focal formation during promotion. Rats fed less than 0.02 p.p.m. selenium had a significantly greater percentage of liver section occupied by foci than rats fed either 0.15 or 1.9 p.p.m. selenium. Feeding 1.9 p.p.m. selenium during promotion did not afford greater protection above the 0.15 p.p.m. level. Hepatic glutathione peroxidase activity at week 15 was significantly diminished in animals fed less than 0.02 p.p.m. selenium during promotion. Feeding 1.9 p.p.m. selenium when compared with 0.15 p.p.m. did not result in a consistent increase in enzyme activity. Although differences were observed in growth due to dietary treatment, there were no significant correlations between preneoplastic foci and body weight, food consumption or food efficiency. These findings indicate an interaction between dietary fat and selenium during initiation, but not during early promotion. Furthermore, dietary selenium and fat may function by different mechanisms at different stages of carcinogenesis.
Carcinogenesis 1987 Jan
PMID:Influence of dietary fat and selenium in initiation and promotion of aflatoxin B1-induced preneoplastic foci in rat liver. 287 48

The regulation of glutathione and various glutathione-dependent enzymes has been studied in two ovarian adenocarcinoma cell lines derived from a patient before (PE01) and after (PE04) the onset of drug resistance to cis-platinum, chlorambucil and 5-fluorouracil. Reduced glutathione levels were higher in the drug resistant cells (PE04). This could possibly be attributed to a much higher (6.5-fold) gamma-glutamyl-transpeptidase activity. In addition, glutathione-S-transferase (GST) and glutathione peroxidase were 2.9- and 2.3-fold higher in this cell line. Analysis of the GST subunit composition showed both cell lines contained high levels of the acidic GST and lower concentrations of a basic isozyme. The difference in GST activity between PE01 and PE04 did not appear to be related to the levels of these GST subunits. GSH, glutathione peroxidase and gamma-glutamylcysteinyl synthetase were all found to be regulated during the cell cycle, higher levels being detected in logarithmic versus confluent cultures of PE01 and PE04 and MCF7. This did affect some of the differences between PE01 and PE04 and therefore may be a contributing factor to the differential sensitivity of these cells to cytotoxic compounds. The above data provide the first evidence that tumour cells obtained from a patient before and after the onset of drug resistance have significant differences in glutathione-dependent enzyme content.
Carcinogenesis 1988 Jul
PMID:Glutathione and glutathione-dependent enzymes in ovarian adenocarcinoma cell lines derived from a patient before and after the onset of drug resistance: intrinsic differences and cell cycle effects. 289 6

The biochemical responses to 8-week supplementary treatment with selenium and/or vitamin E were evaluated in 41 patients with gynaecological cancer during cytotoxic chemotherapy, in Finland, a selenium-deficient country. After the control course of 1-day treatment with cytostat agents, 11 patients received a combination of selenium and vitamin E (sodium selenate, 200 micrograms/day + vitamin E, 300 mg/day), 11 received selenium (sodium selenate, 200 micrograms/day) and seven received vitamin E (300 mg/day) as supplementary therapy, while 12 patients had no supplementary drugs. Sodium selenate alone and combined with vitamin E significantly increased the serum selenium levels, but the activity of serum glutathione peroxidase (GSH-Px) increased significantly only in the selenium- and vitamin E-treated patients with low initial GSH-Px activity. The cytotoxic chemotherapy did not change the activity of GSH-Px, while the concentrations of lipid peroxides decreased. Sodium selenate alone or with vitamin E did not modify this decrease. Sodium selenate alone significantly decreased the capacity of the platelets to produce thromboxane A2; it increased high-density lipoprotein cholesterol levels and prevented the cytotoxic-chemotherapy-associated increase of creatine kinase. Selenium supplementation might thus be beneficial during cytotoxic chemotherapy in ovarian cancer patients with low selenium levels.
Carcinogenesis 1989 Feb
PMID:Supplementation with selenium, vitamin E and their combination in gynaecological cancer during cytotoxic chemotherapy. 291 78

Target organ-specific estrogen-induced DNA adducts were previously shown to precede renal carcinogenesis in Syrian hamsters. Because estrogens induced these DNA modifications, but were not part of the adduct structure, free radical activation of endogenous electrophiles was postulated as a mechanism of tumor induction by estrogens. In the present study, the activities of enzymes which detoxify reactive intermediates were studied in liver and kidney of hamsters treated with estradiol for 1, 2, and 4 mo and in untreated controls. These studies were done to detect oxidative stress in the target organ of carcinogenesis. In the estrogen-exposed hamster kidney (1, 2, and 4 mo), activities of glutathione peroxidases I and II were significantly increased. The activity of catalase was decreased compared to those in untreated controls. In livers which are not the target organ of carcinogenesis, treatment of hamsters with estrogen for 1, 2, and 4 mo resulted in changes of activities of glutathione peroxidases I and II and catalase, which were opposite to the pattern found in the kidney. Activities of superoxide dismutase, glutathione reductase, glucose-6-phosphate dehydrogenase, gamma-glutamyl transpeptidase, and glutathione transferase in estradiol-treated hamster liver and kidney did not differ significantly from those in either liver or kidney of untreated age-matched controls. Fluorescent products of lipid peroxidation more than doubled in the kidney, but not in the liver of hamsters treated with estradiol for 1 mo. It is concluded that the increases in glutathione, in the activity of glutathione peroxidase, and in products of lipid peroxidation in the kidneys of hamsters treated chronically with estrogen all point towards elevated levels of oxidative stress.
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PMID:Changes in activities of free radical detoxifying enzymes in kidneys of male Syrian hamsters treated with estradiol. 292 1

Labeling studies with 75selenium (75Se) have suggested the existence of selenium-binding proteins in addition to glutathione peroxidase (GSH-Px) in rodent tissues. Three selenium-binding proteins of apparent mol. wt 56, 14 and 12K on SDS-PAGE were isolated from mouse liver using Sephadex G-150 and DEAE-Sephadex chromatography. The proteins were electroeluted from SDS-PAGE gels and injected into rabbits to elicit antibodies. Western immunoblot experiments indicated that the 56K protein was distinct from the 14 and 12K proteins. The latter two proteins appeared to be immunologically related, perhaps as differentially processed variants. The 56 and 14/12K proteins appeared to be distinct from GSH-Px and the 57K plasma selenium-binding proteins. These results indicate that the mouse liver contains at least two selenium-binding proteins distinct from GSH-Px. The existence of the antibodies should permit experiments which help to examine the role of these proteins in the biological function of selenium in mammals.
Carcinogenesis 1989 Mar
PMID:Evidence for two selenium-binding proteins distinct from glutathione peroxidase in mouse liver. 292 98

The role of reactive oxygen (RO) in the promotion of neoplastic transformation of JB6 mouse epidermal cells by 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated using inhibitors of RO itself or RO generating systems of seven different types. Bovine erythrocyte CuZn superoxide dismutase (SOD) maximally decreased anchorage-independent (AI) colony induction by TPA in semi-solid agar in a dose-dependent manner to 10% of TPA control level. The inhibitory effect was specifically on induction of transformation, not expression of transformation. Copper (II) (3,5-diisopropylsalicylic acid)2, which exhibits biomimetic SOD activity, was also effective. Two enzyme eliminators of H2O2, catalase and glutathione peroxidase, failed to prevent TPA-promotion. Among three hydroxyl radical scavengers, D-mannitol and Na-benzoate were moderately active but tetramethylurea did not specifically inhibit AI colony induction by TPA. A quencher of singlet oxygen, 1,4-diazobicyclo-[2,2,2]octane was also inactive. Antioxidants blocked AI transformation by TPA moderately (n-propyl gallate and tannic acid) or weakly (BHA). BHT did not specifically inhibit promotion of transformation. The effects of three inhibitors of the arachidonic acid cascade were examined. NDGA and quercetin (lipoxygenase inhibitors) were moderately active but indomethacin (cyclooxygenase inhibitor) was much less active. Based on these results, we suggest that superoxide anion (O2-.) is required for promotion of transformation by TPA. H2O2 and 1O2 appear not to be required. Hydroxyl radicals and lipid peroxides, possibly associated with O2-. action or formed in the course of oxidative metabolism of arachidonic acid also appear to be required but to a lesser extent. Products of the lipoxygenase pathway of arachidonic acid metabolism but not the cycloxygenase pathway may be important in promotion of transformation by TPA in JB6 mouse epidermal cells. The epidermal cells themselves can be both the source of and the target of the reactive oxygen in promotion.
Carcinogenesis 1985 Feb
PMID:Role of reactive oxygen in tumor promotion: implication of superoxide anion in promotion of neoplastic transformation in JB-6 cells by TPA. 298 13

Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
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PMID:Xenobiotic metabolizing enzymes in genetically and chemically initiated mouse liver tumors. 308 73

To better understand the role of free radicals in liver carcinogenesis, endogenous antioxidant defense systems and the susceptibility of membranes to lipid peroxidation were evaluated in early lesions and in malignant tumors induced by the Solt-Farber resistant hepatocyte protocol. These parameters were also measured in the liver surrounding these tumors. In comparison with the normal liver, both nodules and carcinomas show a different biochemical pattern consisting of decreased glutathione peroxidase (GSH peroxidase) and catalase activities plus increased glutathione reductase (GSSG reductase) activity. In contrast, 1 week after the application of the initiation-selection protocol, the liver displays a high level of glutathione (GSH), high GSSG reductase activity, a reduced production of malondialdehyde and no changes in superoxide dismutase and GSH peroxidase activities. These data suggest that the liver is well protected against reactive oxygen species. During the carcinogenic process, the liver parenchyma surrounding the altered foci recovers from most of the modifications induced by the initiation-selection treatment. These results add additional support for the hypothesis that the appearance of early alterations in the liver, after a carcinogenic treatment, might be an adaptive response to a hazardous environment in which selected cell populations are transformed into nodules and/or carcinomas.
Carcinogenesis 1988 Nov
PMID:Analysis of antioxidant defense systems during rat hepatocarcinogenesis. 318 Mar 39

The effect of supplemental inorganic selenium given during the initiation or postinitiation phase of colon carcinogenesis induced by azoxymethane [(AOM)CAS:25843-45-2] was studied in male F344 rats. Weanling animals were raised on AIN-76A semipurified (control) diet. Starting at 4 wk of age, groups of animals intended for initiation study were fed the semipurified diets containing 0.5 and 2.5 ppm selenium in the form of sodium selenite, and those intended for postinitiation study were continued on the control diet. At 7 wk of age, all animals except the vehicle-treated controls were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 wk). One wk following AOM treatment, animals in the initiation study receiving the supplemental selenium were transferred to the control diet whereas those in the postinitiation study receiving the control diet were transferred to the diets containing 0.5 and 2.5 ppm selenium. These animals were continued on this regimen until the termination of the experiment at 34 wk post-AOM injection. Tissue and blood glutathione peroxidase activity was measured in vehicle-treated animals fed the control and selenium-supplemented diets. The results indicate that body weights were comparable among the various dietary groups. Feeding of diets containing 0.5 and 2.5 ppm selenium during the initiation phase had no effect on colon tumor incidence, but the multiplicity of adenomas was slightly inhibited in animals fed the 2.5 ppm selenium diet. The incidence and multiplicity of colon adenocarcinomas and the multiplicity of colon adenomas were inhibited in animals fed the 2.5-ppm selenium diet during the postinitiation phase of carcinogenesis. The incidence of small intestinal tumors was higher in animals fed the 2.5-ppm selenium diet during the initiation phase than in animals fed the control diet and 0.5-ppm selenium diet. Selenium-dependent glutathione peroxidase activity was increased in kidneys and small and large intestinal mucosae of animals fed the 2.5-ppm selenium diet compared to those fed the 0.5-ppm selenium and control diets.
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PMID:Effect of dietary excess of inorganic selenium during initiation and postinitiation phases of colon carcinogenesis in F344 rats. 334 57

In light of recent studies implicating low catalase activities in the pathogenesis of the cancer-prone disease xeroderma pigmentosum (XP) we have measured catalase activity, protein levels, and mRNA concentrations in six XP fibroblast strains and three normal controls. Only one XP strain of complementation group A (XP1223) possessed significantly lower catalase by all three criteria. The other five XP strains (two XP variants, two strains of complementation group D, and one strain of complementation group C) possessed catalase levels which fell into the range of the interindividual variations of normal controls. We further assessed the total enzymatic antioxidant defense status by measuring the levels of copper, zinc, and manganese superoxide dismutase and glutathione peroxidase. None of these enzymes showed significant deviations from controls in XP cells. Our results do not support the notion that a deficient enzymatic antioxidant defense facilitates the establishment of a prooxidant state in XP upon exposure to near-UV. However, they do not argue against the participation of active oxygen in near-UV-induced carcinogenesis in XP.
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PMID:Antioxidant enzymes in xeroderma pigmentosum fibroblasts. 334 84


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