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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased oxidative DNA damage due to increased peroxisomal generation of H2O2 is a potential mechanism in the carcinogenicity of chemical peroxisome proliferators (PP) in rodent liver. In order to determine the relationship between carcinogenicity and peroxisome-dependent DNA damage, levels of DNA base oxidation were examined by comparing 8-hydroxydeoxyguanosine (8-OHdG) in DNA from unfractionated liver of male F344 rats following dietary exposure to PP [WY-14,643, 0.1% or 0.005%; di(2-ethylhexyl)phthalate (DEHP), 1.2%; clofibric acid, 0.5%] or phenobarbital (0.05%). Exposure-related increases in 8-OHdG were not observed at 3 or 11 weeks for any of the compounds fed. At 22 weeks, 8-OHdG was similarly elevated (2-3x) by WY-14,643 (0.1% and 0.005%) and clofibric acid (0.5%). These equivalent increases in 8-OHdG in DNA from unfractionated liver did not parallel the divergent carcinogenicity of these different dietary exposures in the present or previous studies. The potential oxidation of nuclear DNA was examined by comparing levels of 8-OHdG in DNA isolated from purified liver nuclei and unfractionated liver. Elevated levels of 8-OHdG were not detected in DNA isolated from nuclear fractions of livers from rats fed clofibric acid for 22 weeks, indicating the dependence of PP-induced oxidative DNA damage on extranuclear components of samples for DNA isolation. The absence of a quantitative relationship between PP-induced carcinogenicity and oxidative DNA base damage (as 8-OHdG), and the failure to localize this oxidative damage to nuclear DNA, suggest two possible conclusions: (1) quantitation of 8-OHdG, a specific and sensitive indicator of oxidative DNA damage, does not accurately reflect the potential peroxisomal H2O2-dependent DNA damage and carcinogenicity of PP exposure in rodents; (2) other hepatic responses may be more critical features of the mechanism of PP carcinogenicity.
Carcinogenesis 1993 Dec
PMID:Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization. 826 17

High performance liquid chromatography with electrochemical detection (HPLC-EC) was used to measure 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative DNA damage, in mammary gland isolated from tumor-bearing and tumor-free rats fed diets of varied fatty acid composition and vitamin E and selenium content. A method for tissue preparation and analysis is reported and a significant positive correlation shown between degree of unsaturation of dietary fatty acids and 8-OHdG concentration, regardless of antioxidant status. The increase in 8-OHdG concentration with greater fatty acid unsaturation was more pronounced in the absence of adequate dietary vitamin E and selenium. The implications of these data for defining the role of dietary lipid in the process of mammary carcinogenesis are discussed.
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PMID:Antioxidant status and dietary lipid unsaturation modulate oxidative DNA damage. 829 86

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) is present in DNA isolated from human and murine cells. Other studies have reported artificially elevated levels in DNA extracted using phenol-based methods. This report shows that DNA, isolated by different methods, with or without the use of a phenol reagent, contains similar levels of 8-oxodG. This, taken with other studies of human tissues which show varying levels of 8-oxodG, indicates that, with due care in the extraction procedure, biologically significant amounts of this altered base are present in mammalian DNA.
Carcinogenesis 1994 Feb
PMID:7,8-Dihydro-8-oxo-2'-deoxyguanosine present in DNA is not simply an artefact of isolation. 831 37

Long-Evans Cinnamon (LEC) rats, a mutant strain originating from Long-Evans rats, spontaneously develop hereditary hepatitis followed by hepatocellular carcinoma. The hepatic disorder in LEC rats is associated with their abnormal copper metabolism; metal-catalyzed reactions often give rise to oxygen radicals, which may be related to the carcinogenesis. By means of high-pressure liquid chromatography with electrochemical detection, cellular DNA damage caused by oxygen radicals can be assessed in terms of the amount of 8-hydroxydeoxyguanosine (oh8dG). We assayed the amount of oh8dG in DNA of liver, kidneys, and brain of LEC and Long-Evans Agouti (LEA) control rats in seven groups (n = 3 to 6) aged from 5 weeks to 24 months. Control rats, a healthy sibling line, were age-matched. The amount of oh8dG was correlated with the severity of the age-related clinical symptoms in LEC rats. The amount was higher in LEC rats than in the controls, especially in the liver at the acute stage of hepatitis. These findings suggest that oxygen radicals may be important in the carcinogenesis that occurs in LEC rats.
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PMID:Elevated level of 8-hydroxydeoxyguanosine in DNA of liver, kidneys, and brain of Long-Evans Cinnamon rats. 832 Jan 67

Significant differences in sensitivity to multistage carcinogenesis have been noted between mice that are sensitive (SENCAR) and resistant (C57BL/6J) to 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the mechanism of this sensitivity has not yet been established. Recent studies from this laboratory have shown that TPA significantly enhances formation of hydrogen peroxide (H2O2) and oxidized DNA bases in SENCAR mouse skin, as it increases the infiltration of polymorphonuclear leukocytes (PMNs), as quantitated by myeloperoxidase (MPO). In the studies reported here, we compared SENCAR and C57BL/6J mice with respect to TPA-mediated edema, hyperplasia, PMN infiltration, oxidant formation and oxidative DNA damage in mouse skin. Topical application of two TPA doses (2x2-40 micrograms, 20 h apart) dose-dependently increased PMN infiltration and oxidant formation in both mouse strains, which was consistent with TPA-induced morphological alterations (edema and hyperplasia). However, at low TPA doses (2-4 micrograms), the increases over controls in the SENCAR mice were significantly greater (P < 0.01) than those in C57BL/6J mice. Comparison of the net values indicated that 4 micrograms TPA enhanced PMN infiltration (MPO units/cm2) and oxidant formation (nmol H2O2/cm2) in SENCAR mice by 7.7- and 11-fold respectively over those present in TPA-treated C57BL/6J mouse skin. At the same dose, TPA also significantly increased formation of thymidine glycol (dTG; 5.5-fold), 5-hydroxymethyl-2'-deoxyuridine (HMdU; 4.9-fold) and 8-hydroxyl-2-deoxyguanosine (8-OHdG; 11.4-fold) in SENCAR mouse epidermis. Then, the levels of all three declined. In C57BL/6J mice, there were virtually no increases at 4 micrograms TPA, but their levels gradually increased with higher TPA doses and reached maxima at 10 micrograms TPA for dTG (1.9-fold increase), at 20 micrograms TPA for 8-OHdG (6.0-fold), and at 30 micrograms TPA for HMdU (1.8-fold). We conclude that the TPA-mediated oxidative events and oxidative DNA modification by different doses of TPA correlate with the promoting potencies of those doses in both mouse strains. Therefore, they could be, at least in part, responsible for the strain-dependent sensitivity to tumor promotion.
Carcinogenesis 1993 May
PMID:Sensitivity to tumor promotion of SENCAR and C57BL/6J mice correlates with oxidative events and DNA damage. 838 53

Fanconi's anemia (FA) cells are highly susceptible to both reactive oxygen species and mitomycin C (MMC), a DNA cross-linking agent. In this study we have determined the amounts of 8-hydroxydeoxyguanosine (8OHdG), typical of oxidative DNA damage, in Epstein-Barr virus transformed lymphoblasts from FA patients and normal controls by the use of HPLC combined with electrochemical detection. FA cells (HSC72 and 99 cells being assigned to FA complementation group A) formed 2-3 times more 8OHdG than control cells after incubation with 20 mM H2O2 at 37 degrees C for 30 min. FA cells also formed more 8-hydroxyguanosine, typical of oxidative RNA damage, than control cells. FA cells showed decreased activity to decompose H2O2. Although the activity in FA cells was only 20-30% less than control cells, the remaining, undecomposed H2O2 concentration was almost twice as much in FA cells as in control cells, and the remaining H2O2 concentration correlated well with the amounts of 8OHdG formation. The H2O2 decomposing activity was almost completely inhibited by sodium azide (NaN3) or aminotriazole, both catalase inhibitors. With these inhibitors the amounts of 8OHdG formation were much higher than in those cells without inhibitors, and were almost the same in control cells as in FA cells. Catalase activity in FA cell lysates was 70-80% of controls. MMC also increased 8OHdG formation in FA cells only at ED100 but not at ED50. These results indicate that FA cells, at least FA complementation group A cells, have increased susceptibility to oxidative DNA damage, and that this increased susceptibility is possibly due to decreased catalase activity. These results also suggest that catalase plays an important role in protecting DNA from oxidative damage. However, this increased susceptibility to oxidative DNA damage is considered not to be the major cause of the increased susceptibility to MMC.
Carcinogenesis 1993 Jun
PMID:Increased formation of 8-hydroxydeoxyguanosine, an oxidative DNA damage, in lymphoblasts from Fanconi's anemia patients due to possible catalase deficiency. 838 71

DNA damage caused by UV radiation in the presence of riboflavin or hematoporphyrin was characterized by the DNA sequencing technique using 32P-labeled DNA fragments and the analysis of 8-hydroxydeoxyguanosine (8-OH-dG) formation in calf thymus DNA. Exposure of double-stranded DNA to 365 or 302 nm radiation in the presence of riboflavin induced the sequence-specific DNA cleavage which is different from that caused by 302 or 254 nm irradiation in the absence of a sensitizer. The specific cleavage sites were the guanine residues located 5' to guanine. On the other hand, when denatured single-stranded DNA was irradiated at 365 nm with riboflavin or hematoporphyrin, cleavages occurred at most guanine residues. With D2O, the sequence-specific damage of double-stranded DNA by riboflavin was not enhanced, whereas the damage to single-stranded DNA by hematoporphyrin was greatly enhanced. Photodynamic action of riboflavin caused the formation of 8-OH-dG in double-stranded DNA. The enhancing effect of D2O on 8-OH-dG formation was not observed with riboflavin. By contrast, hematoporphyrin plus 365-nm light induced the 8-OH-dG formation only in denatured single-stranded DNA and the 8-OH-dG yield was increased about 2-fold in D2O. ESR spin destruction experiments suggested that photoexcited riboflavin reacts with dGMP to produce riboflavin anion radical and guanine cation radical, but not with other mononucleotides. The estimated ratio of 8-OH-dG yield to total guanine loss indicates that the photoexcited riboflavin induces 8-OH-dG formation specifically at the guanine residue located 5' to guanine through electron transfer. The mechanism was discussed in relation to UV carcinogenesis.
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PMID:8-Hydroxydeoxyguanosine formation at the 5' site of 5'-GG-3' sequences in double-stranded DNA by UV radiation with riboflavin. 839 Apr 59

Peroxisome proliferators are a structurally diverse group of chemicals. They include fibrate hypolipidaemic drugs, phthalate ester plasticisers, phenoxy acid herbicides, azole antifungal drugs, and perflurinated fatty acids. This presentation will focus on the common pleiotropic responses produced by these compounds including hepatomegaly (hyperplasia and hypertrophy), activation of cell cycle S-phase ploidy changes, cytochrome P4504A1 induction, morphometric/biochemical analysis of peroxisome proliferation and stimulation of growth factors, and oncogene activation. Consideration will also be given to the role of recently described Peroxisome Proliferator Activated Receptor in these diverse hepatic responses. Peroxisome proliferators are uniformly negative in a wide range of genotoxicity tests, but nevertheless are complete carcinogens, particularly in rodent liver. Mechanisms of nonmutagenic carcinogenesis will be discussed including the active oxygen hypothesis involving 8-hydroxydeoxyguanosine adducts and the possibility of peroxisome proliferators promoting preexisting lesions by clonal expansion, eventually resulting in frank tumorigenesis. Finally, a consideration of the risk assessment of peroxisome proliferation to humans will be discussed.
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PMID:Peroxisome proliferators: paradigms and prospects. 839 Jul 28

Reactive oxygen species (ROS) have been implicated as being involved in tumor promotion processes. However, the mechanism by which ROS modulate tumor promotion has not as yet been elucidated. In this report, we show that phorbol ester-type tumor promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], mezerein and 12-O-retinoylphorbol-13-acetate [RPA]), which vary in their in vivo potencies, also differ in their effect on formation of hydrogen peroxide (H2O2) and oxidation of normal bases to 5-hydroxymethyl-2'-deoxyuridine [HMdU] and 8-hydroxyl-2'-deoxyguanosine [8-OHdG] in the DNA of SENCAR mouse epidermis, though they are equipotent in causing infiltration of polymorphonuclear leukocytes (PMNs). Treatment of SENCAR mice with the chemopreventive agents (-)-epigallocatechin gallate or tamoxifen (6.5 nmol) prior to application of TPA (6.5 nmol) diminished PMN infiltration, and formation of H2O2, HMdU and 8-OHdG. These results strengthen the evidence that ROS are involved in tumor promotion, and that generation of ROS and the subsequent oxidative DNA modification are related to the tumor-promoting potencies of the different phorbol ester-type promoters.
Carcinogenesis 1993 Jun
PMID:Relationship of oxidative events and DNA oxidation in SENCAR mice to in vivo promoting activity of phorbol ester-type tumor promoters. 850 7

Peroxisome proliferators (POPs), such as hypolipidemic drugs or industrial phthalate ester plasticizers, are widely known as non-genotoxic hepatocarcinogens in rodents. As one of the possible mechanisms of POP-induced carcinogenesis, the "Oxidative Stress" theory has been postulated. In this review, in order to reconsider the significance of "Oxidative Stress" to POP-induced carcinogenesis, we focus on in vivo studies examining formation of 8-hydroxydeoxyguanosine (8-OH-dG), a marker of oxidative DNA damage with mutagenic potential, after treatment of rodents with POPs. Some studies clearly demonstrated that 8-OH-dG levels in the liver DNA were increased by POP-treatments. These findings suggest that "Oxidative Stress" could contribute as one factor to POP-induced carcinogenesis. Furthermore, we refer to other multiple biological changes caused by POP-treatment presumably contributing to the carcinogenic mechanisms, and consider possible roles of "Oxidative Stress" in the carcinogenesis process.
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PMID:Role of oxidative stress in non-genotoxic carcinogenesis with special reference to liver tumors induced by peroxisome proliferators. 856 28


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