Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Numerous hepatic cell lineage pathways have been proposed for the development of hepatocarcinogensis induced by chemical carcinogens in rats. The roles of bile ductule cells and hepatocytes in the development of carcinogenesis were investigated using light and electron microscopic procedures to detect differences in morphology and in the phenotypic expression of antigens that are associated with each cell type. In early stages of hepatocarcinogenesis (4-10 weeks after initiation of feeding of a choline-deficient ethionine containing diet), both bile ductulelike (BDL) cells and hepatocytes were seen in mitosis. At the light microscope level, BDL cells showed intense cytoplasmic pyronin (RNA) staining and were positive for the antigens defined by monoclonal antibody 270.38 (bile ductule cells and "oval" cell marker) and glutathione-S-transferase (Yp isoform), whereas hepatocytes were positive for the antigens defined by monoclonal antibodies 270.26 and 258.26 (liver parenchymal cell markers), catalase activity (peroxisome marker) and adenosine triphospatase activity (bile canalicular marker). The authors frequently encountered BDL cells and hepatocytes in close proximity. Ultrastructural examination showed extensive plasma membrane appositions between a subset of BDL cells and hepatocytes. Desmosome structures, tight junctions, microvilli interdigitations and ATPase-positive bile canalicularlike structures were present along the contiguous plasma membrane domains of BDL cells and hepatocytes. Many of the BDL cells attached to hepatocytes were also attached to other BDL cells that had retained a basal lamina. In many cases, BDL cells connected to both hepatocytes and other BDL cells were no longer completely surrounded by basal lamina and had acquired a dual polarity as a consequence of their sharing apical and lateral membrane domains with both BDL cells and hepatocytes. BDL cells showed increased numbers of microperoxisomes (catalase positive organelles) and numerous free ribosomes. Hepatocytes showed a prominent development of the smooth endoplasmic reticulum, a feature prominent in hepatocytes within hyperplastic nodules. Since BDL cells and hepatocytes proliferate and BDL cells and hepatocytes develop intercellular junction sites, the authors propose that both cell types in early stages of carcinogenesis have the capacity to enter the cell lineage pathway leading to the development of hepatocarcinoma. Furthermore, the finding that BDL cells and hepatocytes form multiple attachment sites at the level of the plasma membrane, suggests the possibility that at some stage convergence of separate hepatic cell pathways may occur.
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PMID:Characterizations of and interactions between bile ductule cells and hepatocytes in early stages of rat hepatocarcinogenesis induced by ethionine. 175 May 8

The involvement of free radicals in the carcinogenic mechanism has been suggested, however, little is known about the role of free radicals in the pancreatic cancer. In this study, the effects of active oxygen on the carcinogenesis of the tumor were examined by measuring the levels of scavengers in pancreatic cancer of Syrian golden hamsters. Pancreatic cancer was induced by di-iso-propanol nitrosamine (500 mg/kg body weight/week x 24 weeks). Activities of superoxide dismutase (SOD), catalase, glutathion peroxide (GSH-Px) and malon dialdehyde (MDA) in the tumor and border zone were compared with those in the non-tumor region and control normal tissue. Activities of SOD and catalase in the tumor and border zone were significantly lowered than those in non-tumor region and normal tissue. GSH-Px levels were significantly higher in the tumor than those in the non-tumor region and normal tissue. MDA levels also tended to be high in the tumor. These results suggest that the development of cancer in pancreatic tissue is related to a reduction of SOD and catalase. GSH-Px and MDA are suggested to be involved in the reactions of free radicals.
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PMID:Role of free radical scavengers in pancreatic carcinomas of hamsters. 182 11

The possibility that the interaction of C-nitroso aromatics with polyunsaturated fatty acids (PUFA) causes lipid peroxidation was investigated through determination of conjugated diene and malodialdehyde (MDA) formation after anaerobic/aerobic vs. aerobic incubations of nitrosobenzene (NOB) or 2-nitrosofluorene (2-NOF) with linoleic, linolenic or arachidonic acid or methyl linolenate. Anaerobic incubation of NOB or 2-NOF with linolenic acid at the molar ratio of 1:1 for 24 h yielded approximately 5.5-13% of the PUFA as conjugated diene which appeared stable upon exposure to air. Interaction of PUFA and 2-NOF or NOB yielded MDA, the amounts of which were significantly greater when 24-h anaerobic preceded 1-6-h aerobic incubation. Furthermore, the differences in the amounts of MDA resulting from 24- and 0-h anaerobic incubations were significantly greater when the molar ratio of 2-NOF (or NOB) to PUFA was increased (2.0 greater than 1.0 greater than 0.5). Superoxide dismutase or catalase had no effect on the yields of MDA following either anaerobic/aerobic or aerobic incubations of PUFA and 2-NOF. EDTA (1 or 10 microM) had no effect on the yields of MDA from aerobic incubations, but it decreased the amounts of MDA (by approximately 30 or 60%, respectively) from anaerobic/aerobic incubations. The data suggested that inhibition by EDTA was due to chelation of trace iron, which following anaerobic interaction of PUFA and 2-NOF might have been reduced to Fe2+ and contributed to the enhanced lipid peroxidation. Thus, adduction of C-nitroso aromatics to PUFA yields radical species which directly and/or via reaction with trace iron lead to lipid peroxidation. The lipophilicity of C-nitroso aromatics suggests that this process may be of consequence in their mutagenesis/carcinogenesis.
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PMID:Interaction of C-nitroso aromatics with polyunsaturated fatty acids: route to lipid peroxidation. 189 3

Sodium nitrite was shown to enhance the metabolism of trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) to 7/8,9,10- and 7,10/8,9-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (tetraols) in phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocytes (PMNs). The production of these tetraols implicates the intermediate formation of the corresponding trans-7,8-dihydroxy-9,10-epoxy-7,8-9,10-tetrahydrobenzo[a]pyrene (anti-BPDE). A 2- to 3-fold increase in the tetraol yield was observed in the presence of nitrite in excess of 1 mM. Sodium azide, an inhibitor of myeloperoxidase and catalase, reduced the nitrite-stimulated metabolism of BP-7,8-diol in PMA-activated leukocytes. Diphenylene iodonium sulphate, a NADPH-oxidase inhibitor, lowered the production of tetraols in PMA-stimulated leukocytes both in the absence and presence of nitrite. Additionally, nitrite markedly enhanced the covalent binding of metabolites derived from [3H](-)-BP-7,8-diol to leukocyte proteins as well as to DNA present extracellularly. The nitrite-stimulated covalent binding to both proteins and DNA was inhibited by the presence of sodium azide. The mechanism underlying the effect of nitrite on the metabolism of BP-7,8-diol to reactive intermediates in PMA-activated human polymorphonuclear leukocytes is not known. However, the results are compatible with a peroxidase-dependent mechanism although other possible pathways may contribute to the enhanced rate of metabolism.
Carcinogenesis 1991 May
PMID:Sodium nitrite-stimulated metabolic activation of benzo[a]pyrene 7,8-dihydrodiol in human polymorphonuclear leukocytes. 202 41

Antioxidant enzyme levels were determined in kidneys during estrogen-induced cortical renal tumorigenesis in male Syrian hamsters. The activity of these enzymes in renal tumors were compared to those in the kidney cortex of untreated male castrated hamsters of different ages and in age-matched animals treated with diethylstilbestrol (DES) for varying periods. A transient increase in kidney Mn superoxide dismutase (MnSOD) and total SOD activity was seen after 1.5 and 3.1 months of DES treatment compared to untreated controls. However, after 4.4 months of DES exposure the activities of these antioxidant enzymes fell below untreated levels. The level of MnSOD and CuZnSOD was 3- to 10-fold lower compared to castrated male renal cortical values in DES-induced primary, serially transplanted and in autonomous renal tumour variants. Catalase activity declined steadily at 1.5 to 4.4 months of DES treatment. Low levels of catalase activity were found in all tumors examined. In general, Western blot analysis of immunoreactive proteins confirmed these findings, indicating that the low enzyme activities were due to low levels of enzyme proteins. Immunohistochemistry of the earliest tumor foci exhibited negligible antioxidant enzyme activity. The levels of these antioxidant enzymes were similar in all tumors surveyed, both primary and autonomous variants and in newborn kidneys, and they were about 10-fold lower than in normal kidney cortex or isolated proximal tubules.
Carcinogenesis 1991 Jun
PMID:Superoxide dismutase and catalase levels during estrogen-induced renal tumorigenesis, in renal tumors and their autonomous variants in the Syrian hamster. 204 4

Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. These highly reactive compounds can act as initiators and/or promoters, cause DNA damage, activate procarcinogens, and alter the cellular antioxidant defense system. Antioxidants, the free radical scavengers, however, are shown to be anticarcinogens. They function as the inhibitors at both initiation and promotion/transformation stage of carcinogenesis and protect cells against oxidative damage. Altered antioxidant enzymes were observed during carcinogenesis or in tumors. When compared to their appropriate normal cell counterparts, tumor cells are always low in manganese superoxide dismutase activity, usually low in copper and zinc superoxide dismutase activity and almost always low in catalase activity. Glutathione peroxidase and glutathione reductase activities are highly variable. In contrast, glutathione S-transferase 7-7 is increased in many tumor cells and in chemically induced preneoplastic rat hepatocyte nodules. Increased glucose-6-phosphate dehydrogenase activity is also found in many tumors. Comprehensive data on free radicals, antioxidant enzymes, and carcinogenesis are reviewed. The role of antioxidant enzymes in carcinogenesis is discussed.
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PMID:Free radicals, antioxidant enzymes, and carcinogenesis. 219 55

Using an initiation--selection--promotion protocol for induction of liver tumors in Wistar rats, the modulating action of various peroxisome proliferators on neoplasia as well as on selected biochemical parameters was studied. After treatment with diethylnitrosamine (DEN), the animals were subsequently subjected to a selection procedure involving feeding of 2-acetylaminofluorene (2-AAF), and in the middle of the 2-AAF treatment, a single necrogenic dose of carbon tetrachloride. Following a recovery period, the rats were fed a diet containing 0.1% nafenopin (NAF), 0.015% perfluorooctanoic acid (PFOA), 0.05% 2,4-dichlorophenoxyacetic acid (2,4-D), 0.05% 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or 0.05% phenobarbital (PB) as a positive control. When the animals were killed, 7 months after initiation, the incidence of hepatocellular carcinoma was 83, 33 and 16% in the animals treated with NAF, PFOA or 2,4,5-T respectively. No cancers were observed in controls, or in the 2,4,-D groups. In comparison with controls, NAF and PFOA caused a 60-and 24-fold increase inthe peroxisomal beta-oxidation of fatty acids respectively, but only about a 2-fold increase in the catalase activity, 2,4-D and/or 2,4,5-T were much less active in this respect, giving approximately a doubling in the rate of fatty acid oxidation. The specific activity of D-amino acid and glycolate oxidases were significantly depressed, whereas the urate oxidase levels were apparently unaffected by the NAF and PFOA treatment. The results suggest that the selective induction of peroxisomal fatty acid oxidation is consistent with the hypothesis that imbalance between H2O2 overproduction and its destruction could play a role in the modulation of hepatocarcinogenesis by peroxisome proliferators.
Carcinogenesis 1990 Nov
PMID:Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin. 222 20

The effects of prolonged dietary administration of peroxisome proliferators, such as clofibrate, bezafibrate and di(2-ethylhexyl)phthalate (DEHP), on hepatic hydrogen peroxide (H2O2) level and on hepatic activities of the enzymes relating to H2O2 metabolism were examined. Male rats were treated for 79 weeks with the above three peroxisome proliferators. The activities of the peroxisomal beta-oxidation and catalase were increased 8- to 20-fold and 2- to 3-fold, respectively, after 2 or 4 weeks of treatment with these peroxisome proliferators. However at 79 weeks the peroxisomal beta-oxidation activity was 3-8 times that of control. The level of catalase activity was kept at approximately 2-fold even after prolonged treatment of peroxisome proliferators. Although the activities of glutathione peroxidase (GSH-Px) and glutathione S-transferase (GST) were decreased 50-60% at 4-12 weeks by the treatment with peroxisome proliferators, from 20 to 79 weeks those activities approached control levels in the case of clofibrate and bezafibrate but not DEHP-fed rats; GSH-Px and GST activities were kept at approximately 40% those of control. However hepatic capacities of H2O2-degrading enzymes, catalase and GSH-Px, apparently exceeded the H2O2-generating levels obtained on the basis of peroxisomal beta-oxidation activities in the livers of control and treated rats throughout the experimental period. The hepatic H2O2 levels increased only slightly but this increase did not correspond to changes in peroxisomal beta-oxidation. Our results suggest that a large part of H2O2 produced by peroxisomal beta-oxidation could be rapidly scavenged by catalase and GSH-Px in the liver of rats treated with peroxisome proliferators.
Carcinogenesis 1990 Mar
PMID:Long-term effects of hypolipidemic peroxisome proliferator administration on hepatic hydrogen peroxide metabolism in rats. 231 Nov 88

A procedure was developed for the per cell estimation of catalase activities in suspensions and cultures of murine epidermal keratinocytes (MEKs). Per cell catalase activity in MEKs cultured in low Ca2+ medium was relatively constant during the proliferation phase of culturing, but increased approximately 100% within 24 h of cessation of cell division. 12-O-Tetradecanoylphorbol-13-acetate (TPA) treatment of proliferating MEKs cultured in low Ca2+ medium resulted in (i) an initial suppression of proliferation, (ii) the accelerated detachment and differentiation of detached MEKs and (iii) a suppression of catalase induction in the detached population. Induction of MEK differentiation by raising the medium Ca2+ concentration resulted in rapid inhibition of cell division and approximately 200% increases in per cell catalase activities. Addition of TPA immediately prior to Ca2+ shift completely suppressed the Ca2(+)-dependent increases in activity. However, the addition of TPA 48 h after the induction of differentiation by Ca2+ shift had no effects on the elevated, pre-existing catalase activities. Per cell catalase activities varied in vivo with the stage of MEK differentiation. Specifically, the lowest and highest per cell activities (approximately 4-fold difference) were measured in enriched basal cell and spinous cell populations respectively. Catalase activity in the more differentiated MEKs was reduced approximately 33% within 24 h of topical treatment of dorsal skin with a promoting dose of TPA. However, catalase activity in enriched basal cell preparations was unaffected. Collectively, these studies demonstrate that per cell catalase activities increase as MEKs differentiate, and that TPA suppresses the increases in catalase activities that normally occur during differentiation.
Carcinogenesis 1990 Jun
PMID:Modulation of catalase activities in murine epidermal cells as a function of differentiation and exposure to 12-O-tetradecanoylphorbol-13-acetate. 234 71

The prostaglandin H synthase (PHS)-catalyzed metabolism of indenestrol A (IA), indenestrol B (IB) and indanestrol (I) and the effects of these compounds on PHS were studied in incubations with ram seminal vesicle microsomes (RSVM) by means of arachidonic acid (20:4)-dependent oxygen consumption and by HPLC analysis of parent compound conversion as well as UV spectroscopy. IA and I were metabolized by PHS via co-oxidation. By analogy with diethylstilbestrol (DES) they stimulated PHS cyclo-oxygenase dose-dependently and became inhibitory at higher concentrations. Cyclo-oxygenase activity determined at 20:4 concentrations ranging from 10 to 70 microM revealed an antioxidant-type of inhibition for IA with IC50 values ranging from 30 to 150 microM. IB, on the other hand, displayed an indomethacin-like type of PHS inhibition with an IC50 value of 20 microM not dependent upon 20:4 concentration which was consistent with the observation that IB inhibited the co-oxidation of DES when initiated with 20:4 but not with hydrogen peroxide. Recovery of IB was incomplete in extracts from incubations with native PHS, but the reaction was neither 20:4 dependent nor inhibited by indomethacin or catalase; it was partially inhibited by eicosatetraynoic acid (ETYA) or by butylhydroxyanisol (BHA). This may indicate affinity of IB for the enzyme protein and conversion of IB other than by a co-oxidation mechanism. UV spectroscopy revealed the formation of a p-quinoid intermediate in incubations with IA, but not with IB or I. The IA-quinone was synthesized and reacted with nucleophiles such as water, methanol, ethanol and mercaptoethanol to adducts which were further characterized by gas chromatography/mass spectrometry. Our data indicate that indanyl derivatives of DES interact differently with PHS and thus could provide a useful tool for future studies on the mechanism of action of tumorigenic stilbene estrogens as well as on the elucidation of the role of PHS-mediated metabolism in their toxic action.
Carcinogenesis 1989 May
PMID:Indanyl analogs of diethylstilbestrol: differential interaction with prostaglandin H synthase. 249 65


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