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

Oxidative DNA damage has been implicated in diverse biological processes including mutagenesis, carcinogenesis, aging, radiation effects, and chemotherapy. We examined the in vitro effect of low concentrations of Cu(II) or H2O2 alone and in combination on supercoiled plasmid DNA. As much as 10(-2) M Cu(II) or 10(-2) M H2O2 alone did not break the DNA. However, a mixture of 10(-6) M Cu(II) plus 10(-5) M H2O2 produced strand breaks and inactivated transforming ability. Strand breakage was proportional to incubation time, temperature, and Cu(II) and H2O2 concentrations. Abasic sites were not detected. Strand breakage was inhibited by metal chelators, catalase, and by high levels of free radical scavengers implying that Cu(II), Cu(I), H2O2, and .OH were involved in the reaction. The extent of DNA strand breakage was not affected by superoxide dismutase indicating that superoxide was not a major contributor to the DNA damage. DNA sequence analysis demonstrated that hot piperidine-sensitive DNA lesions were produced preferentially at sites of 2 or more adjacent guanosine residues. This sequence specificity was observed with Cu(II) plus H2O2 but not with Cu(I) alone. Polyguanosine sequence specificity for DNA damage induction appears to be unique among simple chemical systems. This reaction may be important in mechanisms of oxidative damage in vivo.
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PMID:Site-specific oxidative DNA damage at polyguanosines produced by copper plus hydrogen peroxide. 291 81

Quantitative comparisons of the time course of biochemical and morphological changes induced by peroxisome proliferators resulting in low and high incidences of hepatic cancer have not been conducted previously under bioassay conditions. [4-Chloro-6-(2,3-xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643) at 0.1% in the diet produced a much higher incidence of hepatic cancer in male rats than 1.2% di(2-ethylhexyl)phthalate (DEHP) in the diet. Both diets, however, caused similar degrees of peroxisome proliferation. To investigate this difference in carcinogenicity, H2O2-detoxification mechanisms and indices of oxidative damage were evaluated in male F-344 rats fed 1.2% DEHP or 0.1% Wy-14,643 for up to one year. DEHP or Wy-14,643 treatment increased hepatic catalase activity approximately 25% from 8 to 365 days. DEHP or Wy-14,643 treatment decreased hepatic glutathione peroxidase activity by 50% from 8 to 365 days. Glutathione concentrations were not affected by 151 days of DEHP or Wy-14,643 feeding. The similar effects of DEHP and Wy on H2O2 detoxification enzymes and glutathione concentrations suggests that these factors are not responsible for the widely different carcinogenicities of Wy-14,643 and DEHP. Hepatic vitamin E concentrations were 50% lower in rats receiving Wy-14,643 for 151 days as compared to rats fed DEHP or control diets. Lipofuscin, which was contained within lysosomes, was increased 3-fold after 39 days of DEHP and remained at this level up to 365 days of treatment. In comparison, lipofuscin was increased 4-fold after 18 days of Wy-14,643 and continued to accumulate in a linear manner reaching values 30-fold over controls after 365 days of treatment. DEHP treatment for 39-365 days increased the activities of the lysosomal enzymes alpha-fucosidase, beta-galactosidase and N-acetylglucosaminidase 50-100%. The same enzyme activities were increased approximately 4-fold after 39-365 days of Wy-14,643. Lysosomal cathepsin B activity was unchanged by DEHP but doubled by 151 and 365 days of Wy-14,643. Acid phosphatase activity was unchanged by DEHP but increased by 50% after 151 and 365 days of Wy-14,643. In addition, conjugated dienes were increased (approximately 45%) only in rats receiving Wy-14,643 for 151 and 365 days. These data show for the first time that the magnitude and time course of lipofuscin deposition, induction of lysosomal enzymes and conjugated diene accumulation, is correlated closely with the degree of carcinogenicity. Wy-14,643-induced decreases in hepatic vitamin E concentrations could contribute to the observed accumulation of conjugated dienes at later time points.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1989 Mar
PMID:Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643. 292 96

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

Multiple lines of evidence show that oxidation products of ascorbic acid (vitamin C) are capable of inducing a variety of genetic alterations in microbial and mammalian cells. We have studied the inactivation kinetics in repair proficient and deficient Escherichia coli K12 cells treated with oxidized solutions of ascorbic acid, in the presence of catalytic amounts of copper. Our results suggest that the repair pathways controlled by the recA and uvrA gene products (the latter in a recA strain) contribute to cell survival. However, the lack of beta-galactosidase induction, in the SOS chromotest, implies a role for the RecA protein other than SOS induction. Catalase and thiourea suppress the toxic effects of oxidized ascorbate solutions, confirming that H2O2 and hydroxyl radicals are intermediate agents in the damaging action. Single-strand breaks were detected in DNA from treated cells.
Carcinogenesis 1986 Feb
PMID:Ascorbate-copper induced DNA lesions and repair in Escherichia coli K12 cells. 300 73

Chronic inflammation has long been associated with carcinogenesis. Phorbol esters which are potent promoters of tumors in mouse skin are also potent inflammatory agents in skin and cause inflammatory cells to release large quantities of reactive oxygen intermediates and oxidized lipid products. SENCAR mice have been bred for their sensitivity to the promotion of tumors by phorbol esters and C57BL/6 mice have been shown to be resistant. We quantified the release of H2O2 and metabolites of arachidonic acid by macrophages obtained from SENCAR and C57BL/6 mice, following exposure to phorbol esters and other stimulants. The basal level for secretion of H2O2 in resident peritoneal macrophages was negligible in cells from both strains. Conversely, inflammatory macrophages from SENCAR mice, elicited by the injection of sterile casein, secreted 4 times more H2O2 than the corresponding cells from C57BL/6 mice. Furthermore, cells from SENCAR mice required less than one-third the amount of phorbol ester to obtain 50% of the maximal response than that required by cells from C57BL/6 mice. This difference was less when zymosan was used as a stimulant. Both resident and inflammatory macrophages from SENCAR mice released more metabolites of arachidonic acid than cells from C57BL/6 mice when exposed to phorbol esters, but macrophages from C57BL/6 mice released more metabolites when stimulated with zymosan. Few differences in the pattern of released metabolites were noted between the strains of mice. There were large differences in the relative amounts of individual metabolites released when different stimulants were used. The enhanced response to phorbol esters of chronic inflammatory cells from SENCAR mice correlates with the enhanced sensitivity to the promotion of tumors by phorbol esters in these animals.
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PMID:Enhanced release of hydrogen peroxide and metabolites of arachidonic acid by macrophages from SENCAR mice following stimulation with phorbol esters. 301 32

We briefly review current concepts with regard to the nature of oxygen-derived oxidants in biological systems. Of these substances, hydroxyl radicals derived from hydrogen peroxide seem most likely to be involved in the various stages of carcinogenesis. Hydrogen peroxide detoxification, primarily through glutathione activity, is essential in preventing hydroxyl-radical formation. Transition metals such as iron play a central role in this latter process. Alterations in cellular macromolecules are most likely to take place if hydroxyl-radical formation is directed toward specific intramolecular sites by appropriately sequestered metals. For this reason, repair and turnover events are apt to be more important protective devices than are the actions of molecules which scavenge hydroxyl radicals. Although many cellular constituents are potential targets in free-radical and oxidant attacks leading to carcinogenesis, nucleic acids have been most extensively studied in this connection. On the basis of these investigations, it is a facile conclusion that oxidants might be involved in the early events of carcinogenesis as well as in transformation or promotion. The literature on antioxidants in chemoprevention in animals is supportive of such a role. However, other biochemical effects of antioxidants should raise a note of caution in the interpretation of animal experiments.
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PMID:The nature of oxidants and antioxidant systems in the inhibition of mutation and cancer. 305 67

Ethanol, potassium metabisulfite, formaldehyde and hydrogen peroxide were tested for tumor-promoting activity in a two-stage stomach carcinogenesis experiment. Male outbred Wistar rats were given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/liter) and a diet supplemented with 10% sodium chloride for 8 weeks. Thereafter, they were maintained on drinking water containing either 10% ethanol, 1% potassium metabisulfite, 0.5% formalin (formaldehyde) or 1% hydrogen peroxide for 32 weeks and then sacrificed for necropsy and histological examination. In the pylorus of the glandular stomach, potassium metabisulfite and formaldehyde significantly increased the incidence of adenocarcinoma after initiation with MNNG and sodium chloride. Hydrogen peroxide did not enhance the tumor yield, and ethanol showed a tendency to decrease neoplastic development. In the forestomach the incidence of squamous cell papilloma was significantly increased in the groups given hydrogen peroxide or formaldehyde, irrespective of prior initiation. Duodenal adenocarcinoma was induced by the initiation alone (10%) and the incidence was not affected by the subsequent treatments. The results indicate that potassium metabisulfite and formaldehyde both exert tumor-promoting activity in the rat glandular stomach.
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PMID:Effects of ethanol, potassium metabisulfite, formaldehyde and hydrogen peroxide on gastric carcinogenesis in rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine. 308 23

Inflammation and the release of potentially damaging substances, such as reactive oxygen intermediates (ROI) and lipid oxidation products from inflammatory cells, have been linked to the potentiation of carcinogenesis. Murine macrophages when stimulated with phorbol esters induce 5,6 ring saturated thymine residues (T'), a lesion of known oxidative origin, in co-cultivated mammalian cells. Induction of this damage was inhibited by catalase and induced in target cells by reagent H2O2 alone. In the present studies, we used defined populations of macrophages with high, low and intermediate capacities for the release of H2O2 or metabolites of arachidonic acid (AA) to assess the relative contribution of these classes of compounds to the induction of saturated thymines. Macrophages activated with Bacillus Calmette-Guerin (BCG), which have the highest capacity for the release of H2O2 and the lowest for the release of metabolites of AA, induced the lowest levels of saturated thymines. Resident macrophages from the unmanipulated peritoneum, which have the lowest capacity for the production of H2O2 and the highest capacity for release of AA metabolites, induced more saturated thymines than did the BCG macrophages. Inflammatory macrophages elicited by casein, which have an intermediate capacity for release of H2O2 and AA metabolites, induced the highest level of saturated thymines. Zymosan, which induced more release of AA metabolites than release of H2O2, was a better stimulant for the induction of T' than TPA, which is a better stimulant for secretion of H2O2. Nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase and cyclooxygenase pathways for metabolism of AA, inhibited the induction of T' by resident macrophages. Indomethacin, an inhibitor of the cyclo-oxygenase path, enhanced induction of T'. Taken together, the data suggest that while H2O2 has the capacity to induce T' in 3T3 cells, it may not be the only mediator of DNA damage and that lipoxygenase generated metabolites of AA may (alone or in concert with ROI) play an important role in the induction of oxidative DNA damage by macrophages.
Carcinogenesis 1986 May
PMID:The effect of macrophage development on the release of reactive oxygen intermediates and lipid oxidation products, and their ability to induce oxidative DNA damage in mammalian cells. 308 20

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.
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PMID:Effects of combined treatments with selenium, glutathione, and vitamin E on glutathione peroxidase activity, ornithine decarboxylase induction, and complete and multistage carcinogenesis in mouse skin. 309 11

The effects of twice weekly topical applications of hydrogen peroxide on the buccal epithelium of Syrian hamsters were studied. Animals were treated either with hydrogen peroxide alone, with hydrogen peroxide and the carcinogen 9, 10-dimethyl-1,2-benzanthracene (DMBA), or with DMBA alone. In animals treated with 30% H2O2 alone, histopathologic examination after 22 weeks revealed hyperkeratosis and hyperplasia in all animals with hyperchromatic cells and mild dysplasia in four of nine: no tumors were seen. In animals treated with DMBA alone, three of seven (43%) developed epidermoid carcinoma, while six of 11 (55%) of animals treated with DMBA plus 3% hydrogen peroxide and five of five (100%) of animals treated with DMBA plus 30% hydrogen peroxide (P = 0.054) developed carcinoma. Thus, hydrogen peroxide can, by itself, induce pathologic changes frequently associated with preneoplastic lesions; it may also augment carcinogenesis associated with DMBA.
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PMID:Effects of hydrogen peroxide on oral carcinogenesis in hamsters. 310 70


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