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 four 2'-deoxyribonucleosides were gamma-irradiated or were aerobically treated with Fenton-type-reagents, Fe(II)-EDTA or a renal carcinogen Fe(II)-nitrilotriacetic acid (NTA) under the neutral conditions. The reaction mixtures were immediately analyzed by reverse-phase HPLC. Major products detected were 2-hydroxydeoxyadenosine (2-OH-dA), 8,5'-cyclodeoxyadenosine (cyclo-dA), 8-hydroxydeoxyadenosine (8-OH-dA). 5-formyldeoxyuridine (5-CHO-dU), 5-hydroxydeoxycytidine (5-OH-dC), 8-hydroxydeoxyguanosine (8-OH-dG), 8,5'-cyclodeoxyguanosine (cyclo-dG), and glyoxal and its adduct with dG. Ratio of these oxidized products were dramatically changed depending upon the agents used. For example, 2-OH-dA was a modified nucleoside produced most efficiently by Fe(II)-EDTA, while 5-CHO-dU and 5-OH-dC were the major products by the Fe(II)-NTA treatment and gamma-irradiation, respectively. Glyoxal itself was estimated to be produced most frequently (13 folds of 8-OH-dG) when treated with Fe(II)-EDTA, but its formation was not detected by the treatment with Fe(II)-NTA or by gamma-irradiation. 8-OH-dA was not produced by Fe-EDTA or Fe-NTA but was produced by gamma-irradiation. In contrast, 2-OH-dA was not produced by gamma-irradiation. These results suggest that triphosphates of 2-OH-dA, cyclo-dA, 8-OH-dA, cyclo-dG, 5-CHO-dU, 5-OH-dC, and glyoxal-dG as well as 8-OH-dG may be produced in cells with different ratio by various types of oxidative stress and involved in mutagenesis and carcinogenesis.
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PMID:Comparison of oxidation products from DNA components by gamma-irradiation and Fenton-type reactions. 928 65

To evaluate the effect of cigarette smoking on oxidative stress in lung tissues, we compared the levels of a type of oxidative DNA damage, 8-hydroxydeoxyguanosine (8-OH-dG), in tissue obtained from the central sites of lungs from 14 current smokers, seven ex-smokers and nine non-smokers. The mean level of 8-OH-dG in the lung tissues from smokers was 1.43-fold higher than that of the non-smokers (the difference was statistically significant, P = 0.0262). A positive correlation between the 8-OH-dG levels in normal lung tissues and the Brinkman index was obtained from smokers and ex-smokers (r = 0.525; P = 0.0134). A positive correlation was also obtained for the 8-OH-dG levels in normal lung tissues and the number of cigarettes smoked per day (r = 0.436; P = 0.0132). These results suggest that oxidative DNA damage is induced in lung DNA by cigarette smoking.
Carcinogenesis 1997 Sep
PMID:Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site of the human lung. 932 73

Previously, we have reported that aspirin, a cyclooxygenase (COX) inhibitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transferase placental form (GST-P)-positive preneoplastic liver nodules, caused by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. In the present study, in order to elucidate the role of COX pathway in liver lesion-induction by a CDAA diet, the modulatory effects of other distinct chemical classes of COX inhibitors were examined. A long-acting example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) and the short-acting ibuprofen (IBU) (at doses of 0.02, 0.04 and 0.06%) and indomethacin (IND) (at doses of 0.005 and 0.008%) were administered in the CDAA diet to male F344 rats, and animals were killed after 12 and 30 weeks. In another experiment, IND was given in drinking water at doses of 0.001, 0.002 and 0.004%. None of the inhibitors affected the development of fatty liver caused by a CDAA diet, but PIRO at doses higher than 0.04%, strongly inhibited the development of GST-P-positive and neoplastic nodules as well as fibrosis, cirrhosis and formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. With IND, there was only a tendency for inhibition with no clear dose-dependence. The results together with our previous findings, indicate that relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatocarcinogenesis associated with a CDAA diet, although not the development of a fatty liver, suggesting that an augmented COX pathway might play key roles in the causation of liver lesions in this model.
Carcinogenesis 1997 Oct
PMID:Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats. 936 1

We have investigated the mutagenicity of oxidative DNA damage induced in V79 Chinese hamster lung fibroblast, and measured 8-hydroxydeoxyguanosine (8OHdG) levels as an indicator of this damage. A hydroxyl radical generator, N,N'-bis(2-hydroxyperoxy-2-methoxyethyl)-1,4,5,8-naphthalene-tetra -carboxylic-diimide (NP-III), induced 8OHdG in V79 upon irradiation with 366 nm ultraviolet light (UV) for 15 min. 8OHdG was determined by HPLC with electrochemical detection after anaerobic sample processing. The 8OHdG level in the cells treated without NP-III was 0.49 per 10(5) dG, whereas levels in the cells treated with 5, 10 or 20 microM NP-III and UV irradiation were 1.84, 4.06 or 6.95 per 10(5) dG, respectively. The 8OHdG induced by 20 microM NP-III with UV irradiation decreased rapidly, and the half-life of the induced 8OHdG was approximately 6 h. NP-III with UV irradiation also induced DNA strand breaks in all cells uniformly, as determined by single cell gel assay. Mutant frequencies at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in V79 were determined as the number of 6-thioguanine-resistant cells per 10(6) cells. Mutant frequency of the cells without NP-III was 8.0, and frequencies of the cells treated with 5, 10 or 20 microM NP-III and UV irradiation were 14.9, 20.6 or 24.7 respectively. Treatment with 20 microM NP-III and UV irradiation decreased the cell number, determined 3 days after the treatment, to 20.8%. These findings indicate that acutely induced oxidative DNA damage including mutagenic 8OHdG is only weakly mutagenic in V79.
Carcinogenesis 1997 Nov
PMID:Mutagenicity of oxidative DNA damage in Chinese hamster V79 cells. 939 1

8-Hydroxy-2'-deoxyguanosine (8-OH-dG) is a biomarker for oxidative stress on DNA, a common lesion in mammalian cells. A correlation between increased levels of 8-OH-dG and diseases like diabetes, infections and cystic fibrosis has been found in humans. 8-OH-dG levels have been shown to be decreased by antioxidants, an indication of the importance of dietary habits. 8-OH-dG is used as a biomarker for oxidative stress in vivo as well as in vitro and is suggested to be a mutagenic DNA lesion. Different methods are used for the analyses of 8-OH-dG, i.e. GC-MS, HPLC-EC and 32P-postlabeling. The most commonly used method is HPLC-EC. In the analysis of 8-OH-dG, the work-up procedure for DNA, as well as the preparation for analysis, are of critical importance as there is a risk for auto-oxidation of deoxyguanosine (dG), which would result in false high background levels and low sensitivity in analysis. 32P-Postlabeling has recently been applied to the analysis of 8-OH-dG and has shown to be a very sensitive method for the detection of DNA adducts. It is shown here that after extrapolation to normal 32P-postlabeling conditions, [32P]ATP generated 8-OH-dG to levels of 25 8-OH-dG/10(5) dG. [32P]ATP mediated the formation of 8-OH-dG from dG in a dose-dependent manner at all dose levels (0.13-12 microCi). The reaction occurred immediately and increased with time in a linear dose-response fashion. At high doses (6.0 and 12 microCi) the dose-response declined after 24 h, which indicates a possible decomposition or rearrangement of 8-OH-dG. A repeated experiment with 5 microCi [32P]ATP during 2 h resulted in a linear formation of 8-OH-dG and a level of 19 8-OH-dG/10(5) dG. The results indicated that awareness of the auto-oxidation generated by 32P[ATP] in the postlabeling assay is of utmost importance and that dG must be separated before 32P-postlabeling of 8-OH-dG.
Carcinogenesis 1997 Dec
PMID:[32P]ATP mediates formation of 8-hydroxy-2'-deoxyguanosine from 2'-deoxyguanosine, a possible problem in the 32P-postlabeling assay. 945 Apr 89

Arsenicals are epidemiologically significant chemicals in relation to induction of liver cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenicals in mammals, in a rat liver carcinogenesis model. In experiment 1, glutathione-S-transferase placental form (GST-P)-positive foci, putative preneoplastic lesions, were employed as endpoints of a liver medium-term bioassay for carcinogens (Ito test). Starting 2 weeks after initiation with diethylnitrosamine, male F344 rats were treated with 0, 25, 50 or 100 ppm of DMAA in the drinking water for 6 weeks. All animals underwent two-thirds partial hepatectomy at week 3 after initiation. Examination of liver sections after termination at 8 weeks revealed dose-dependent increases in the numbers and areas of GST-P-positive foci in DMAA-treated rats as compared with controls. In experiment 2, ornithine decarboxylase activity, which is a biomarker of cell proliferation, was found to be significantly increased in the livers of rats treated with DMAA. In experiment 3, formation of 8-hydroxydeoxyguanosine, which is a marker of oxygen radical-mediated DNA damage, was significantly increased after administration of DMAA. These results indicate that DMAA has the potential to promote rat liver carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals.
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PMID:Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver. 947 32

N-Ethyl-N-hydroxyethylnitrosamine (EHEN) is known to induce renal and liver tumors in rodents. Recent reports have indicated the formation of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative DNA product, induced by various carcinogens. In the present study, to examine whether oxygen radicals are involved in tumorigenesis induced by EHEN, we investigated the formation and localization of 8-OHdG in kidney, liver and lung of rats. The effects of reduced glutathione (GSH) and diethylmaleate on these responses were also studied. Multiple doses of EHEN administrations (250, 500 or 750 mg/kg, i.p.) resulted in a significant elevation of the 8-OHdG level in kidney DNA in a dose-dependent manner and the formation of 8-OHdG reached the maximal level at 1-2 h after EHEN injection and recovered to the control level at 4 h. On the other hand, no increase in the 8-OHdG level was observed in the DNA of liver and lung. Combined pre- and post-treatment of rats with 2 x 800 mg/kg of GSH i.p. inhibited the elevation of the 8-OHdG level induced by EHEN. Pre-treatment with 0.3 ml/kg of diethylmaleate i.p. increased the formation of 8-OHdG. In the immunohistochemical examinations of rats treated with EHEN (750 mg/kg, i.p.), nuclear expression of 8-OHdG was detected in the epithelial cells of renal cortex, while no induction was observed in liver and lung. These findings suggest that the formation of 8-OHdG by active oxygen species may be an important factor in the initiation of EHEN-induced kidney carcinogenesis.
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PMID:Formation of 8-hydroxydeoxyguanosine in rat kidney DNA after administration of N-ethyl-N-hydroxyethylnitrosamine. 950 Jan 99

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti-beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8-OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.
Carcinogenesis 1998 Mar
PMID:Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion. 952 79

It has been assumed that oxidative damage, including formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts in kidney DNA due to potassium bromate (KBrO3), a renal carcinogen to both sexes of rats, is involved in its mechanisms of tumor induction. However, despite the presumed existence of a repair enzyme(s) for 8-OHdG, there have been no reports demonstrating the changes in adduct levels during medium- or long-term exposure. To elucidate the actual kinetics regarding this parameter during the early stages of KBrO3 carcinogenesis, we measured 8-OHdG levels in kidney DNA together with cell proliferation in renal tubules in both sexes of rats receiving KBrO3 at a dose of 500 ppm in the drinking water for 1, 2, 3, 4, and 13 weeks. Rapid elevation of 8-OHdG levels was noted in treated male rats which persisted until the end of the experiment. Increased cell proliferation in the proximal convoluted tubules was also observed throughout the experimental period, concomitant with alpha2mu-globulin accumulation. Increase in 8-OHdG levels in treated females first became apparent 3 weeks after the start of exposure, with cell proliferation only elevated at the 13-week time point. The present study, employing the same route and dose of KBrO3 known to cause tumors, strongly suggested the requirement of persistent increase of 8-OHdG for neoplastic conversion. Moreover, a clear sex difference in susceptibility to generation of oxidative stress in kidney DNA was found, in addition to alpha2mu-globulin-dependent variation in cell proliferation in the renal tubules.
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PMID:Oxidative DNA damage and cell proliferation in kidneys of male and female rats during 13-weeks exposure to potassium bromate (KBrO3). 963 11

Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens which have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have produced a transgenic mouse line that has elevated catalase activity specifically in the liver. In this study, we have examined if catalase overexpression influences the induction of lipid peroxidation or oxidative DNA damage, two mechanisms which have been hypothesized to be important in the carcinogenesis by peroxisome proliferators. Transgenic mice or non-transgenic litter mates were fed either 0.01% ciprofibrate or a control diet for 21 days. The activities of fatty acyl CoA oxidase and lauric acid hydroxylase were not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. Hepatic lipid peroxidation was estimated by quantifying the concentrations of malondialdehyde and conjugated dienes. Ciprofibrate treatment did not affect either endpoint, but catalase overexpression increased the concentrations of malondialdehyde (in untreated mice only) and conjugated dienes (in both untreated and ciprofibrate-fed mice). Oxidative DNA damage was estimated by quantifying 8-hydroxydeoxyguanosine (8-OHdG) by high-performance liquid chromatography/electrochemical detection. Ciprofibrate treatment significantly increased hepatic 8-OHdG concentrations, in agreement with several previous studies, but catalase overexpression did not significantly affect them, although 8-OHdG concentrations were decreased 50% in untreated mice. These results imply that the metabolism of hydrogen peroxide by catalase is not an important factor in the development of hepatic lipid peroxidation. The decrease in hepatic 8-OHdG in untreated transgenic mice and the increase seen after ciprofibrate administration imply that hydrogen peroxide is important in the formation of 8-OHdG. While the lack of decreased 8-OHdG levels in ciprofibrate-treated transgenic mice does not support this conclusion, it is possible that catalase levels were not sufficiently high to affect this endpoint. Transgenic mice with higher hepatic catalase activities may be required to resolve this issue.
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PMID:Effect of the peroxisome proliferator ciprofibrate on lipid peroxidation and 8-hydroxydeoxyguanosine formation in transgenic mice with elevated hepatic catalase activity. 964 Dec 60


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