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

Oxygen radicals are produced by ionizing radiation and many other environmental carcinogens. They are also produced in cells endogenously by the oxygen metabolism. Therefore it appears to be important to study DNA damage by oxygen radicals and its relation with mutagenesis and carcinogenesis. During a study on DNA damage caused in vitro by heated carbohydrates, which were being used as a model of cooked foods, a new type of DNA modification was discovered, the formation 8-hydroxyguanine (8-OH-Gua). Various oxygen radical forming carcinogenic agents (radiation, cigarette smoke components, asbestos + H2O2 etc.) have been found to be effective in the formation of 8-OH-Gua in DNA in vitro. The formation of 8-OH-Gua was also observed in cellular DNA in vivo after mice or cultured cells were irradiated by ionizing radiation. The 8-OH-Gua residue in DNA may cause mutagenesis and carcinogenesis, since 8-OH-Gua in DNA induces misreading during DNA synthesis in vitro. Among the various types of DNA damage induced by oxygen radicals, 8-OH-Gua can be most readily measured at high sensitivity by high-pressure liquid chromatography coupled to an electrochemical detector. Recently, we found that oral administration of several chemical carcinogens, which are known to produce oxygen radicals, induce 8-OH-Gua in rat target organ DNA. Therefore, 8-OH-Gua can be used as a marker for monitoring oxidative DNA damage as a means of evaluating the carcinogenic potency of various oxygen radical forming agents. We are also measuring 8-OH-Gua levels in human lymphocyte DNA in order to investigate the relation between oxidative DNA damage and the incidence of cancer.
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PMID:[DNA damage by oxygen radicals and carcinogenesis]. 265 Jun 27

Peroxisome proliferators are considered as a novel class of hepatocarcinogenic agents because of their non-mutagenic nature and their ability to cause a significant increase in the levels of hydrogen peroxide generating peroxisomal fatty acid beta-oxidation enzyme system in the liver. Sustained increase in the number of peroxisomes in liver has been shown to induce oxidative stress in the liver. Increased levels of H2O2 generation, hydroxyl free-radical formation, lipid peroxidation and accumulation of lipofuscin are found in the livers of rats following long-term treatment with peroxisome proliferators. Recent evidence indicates the presence of 8-hydroxydeoxyguanosine in the liver DNA of rats chronically treated with a peroxisome proliferator suggesting that this may be the basis for carcinogenesis by this class of non-mutagenic carcinogens.
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PMID:Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis. 267 2

The tobacco-specific N-nitrosamines (TSNA) have been implicated in oral cancer. However, except for one study using rats, no study has shown the ability of TSNA in inducing oral tumours in experimental animals. We have studied the carcinogenic potentials of N'-nitrosonornicotine (NNN) and 4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice and hamsters, wherein the nitrosamines were administered on the tongues of the mice and the cheek pouches of the hamsters to simulate the exposure conditions of humans. It was observed that in Swiss and BALB/c male mice, both NNN and NNK induced tumours of lung, forestomach and liver. However, no oral tumours were induced in mice. The effect of vitamin A depletion was tested in Swiss male mice. It was found that a low vitamin A status did not alter the percentage incidence of tumours induced by both nitrosamines to a significant extent. In the studies using Syrian golden hamsters, long-term treatment of NNK to hamster cheek pouch induced tumours in the lung, liver, stomach and cheek pouch. Subsequently, the effect of hydrogen peroxide (H2O2) on NNK-induced carcinogenicity in hamsters was studied. It was observed that simultaneous administration of NNK and H2O2 to the animals increased the incidence of cheek pouch tumours. Another pertinent observation was that even when a small initiator dose of NNK was given followed by the application of H2O2, a very significant increase in the tumour incidence was observed. This observation suggests that H2O2 could act as a promoter to NNK-induced carcinogenesis. In conclusion it may be stated that both NNN and NNK do not show any strain or species specificity. They failed to produce tumours at the site of application in mice but in hamsters few cheek pouch tumours were seen or were induced when NNK was applied alone. The cheek pouch tumour incidence increased when H2O2 was given concurrently or when applied for a long period after a low initiator dose of NNK was administered in the cheek pouch.
Carcinogenesis 1989 Nov
PMID:Carcinogenicity studies on the two tobacco-specific N-nitrosamines, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 268 Jan 42

DNA damage induced by Ni(II) plus H2O2 was investigated by a DNA sequencing technique using 32P-5'-end-labeled DNA fragments obtained from human c-Ha-ras-1 protooncogene. Ni(II) induced strong DNA cleavage in the presence of H2O2 even without piperidine treatment. Piperidine-labile sites were induced frequently at cytosine, thymine and guanine residues, and rarely at adenine residue. Diethylene-triamine N,N,N',N",N"-pentaacetic acid inhibited the DNA damage. In experiments with singlet oxygen scavengers, sodium azide and dGMP inhibited the DNA damage completely, whereas neither 1,4-diazabicyclo[2.2.2]octane nor dimethylfuran inhibited it. Among hydroxyl radical scavengers, dimethylsulfoxide and sodium formate inhibited the DNA damage considerably, whereas ethanol and mannitol did not. Methionine and methional inhibited the DNA damage completely. The results suggest that Ni(II) ion binds to DNA and subsequently reacts with H2O2 to form active species, which cause DNA damage. The possibility of Ni(II) plus H2O2-mediated DNA damage in vivo is discussed relative to the molecular mechanism of nickel carcinogenesis.
Carcinogenesis 1989 Dec
PMID:Site-specific DNA damage induced by nickel(II) ion in the presence of hydrogen peroxide. 268 51

The radiomimetic agent hydrogen peroxide is known to produce DNA strand breaks, chromosome damage and cell death. It has also been identified as one of the cytotoxic agents formed during certain drug metabolism and by phagocytic cells in the respiratory burst. Our laboratory recently identified the ultimate reactive species responsible for the DNA-damaging and cytotoxic effect of H2O2 as being hydroxyl radical. This was achieved by the use of the specific iron chelator o-phenanthroline, which prevents the occurrence of a Fenton reaction between H2O2 and chromatin bound ferrous ions. In this paper we show that H2O2 is able to induce mutation at the HGPRT locus in V79 cells and morphological transformation of C3H/10T1/2 cells. o-Phenanthroline abolishes both effects, indicating that hydroxyl radical is directly involved in mutation and carcinogenesis.
Carcinogenesis 1989 Jun
PMID:o-phenanthroline protects mammalian cells from hydrogen peroxide-induced gene mutation and morphological transformation. 272 Aug 99

Reactive oxygen species have been shown in several systems to have a role in tumor promotion and carcinogenesis, although the exact mechanisms are yet to be elucidated. To investigate this further, the effect of hydrogen peroxide was studied in a hamster tracheal organ explant epithelial model. Hydrogen peroxide was added exogenously to tracheal explants maintained in defined serum free media at concentrations of 50, 100, 500 or 1000 microM daily for 1 h for a period of two weeks. The explants were then examined using scanning electron microscopy for evidence of morphologic alteration and for the development of squamous metaplasia. Control tracheal explants maintained in serum free media exhibited normal morphology (except for some decrease in the number of ciliated cells) and developed minimal squamous metaplasia after four weeks in culture. At concentrations of 500 and 1000 microM, hydrogen peroxide was toxic to the epithelium, resulting in complete necrosis of the epithelium within seven days. At concentrations of 50 and 100 microM, hydrogen peroxide treatment resulted within three weeks in the development of a significant degree of squamous metaplasia (covering 52 and 48.7%, respectively, of the surface epithelium). This effect could be negated by the exogenous addition of catalase. This model should be useful in the study of the early cellular events following oxidant injury that contribute to the development of squamous metaplasia.
Carcinogenesis 1989 Oct
PMID:Hydrogen peroxide induces squamous metaplasia in a hamster tracheal organ explant culture model. 279 Dec 9

We have measured the capacity of highly-purified, paraffin oil-elicited neutrophils to induce DNA single-strand breaks in a newly established plasmacytoma cell line, RIMPC 2304, which was induced by a retrovirus containing the c-myc and V-Ha-ras oncogenes. This cell line effectively repairs DNA damage induced by gamma-irradiation. DNA damage induced by neutrophils was correlated with the oxidative burst of the neutrophils. The levels of superoxide anion, H2O2, and HOCl produced after stimulation of the neutrophils (6 X 10(5)/cm3) with the tumor promoter phorbol myristate acetate (100 nM) were 33.8 microM, 12.8 microM and 1.7 microM respectively in 15 min, and 98 microM, 20 microM and 8.7 microM respectively in 90 min. The results of alkaline elution experiments revealed that when the same concentration of neutrophils was co-incubated for 15 min in serum-free medium with an equal number of radioactively labeled RIMPC 2304 cells, the latter incurred a level of damage that approximated that caused by 300 rad equivalents of gamma-irradiation or by a 1-min treatment with 20 microM H2O2 at 37 degrees C. Damage from neutrophils was coincident with the oxidative burst; it was induced rapidly (within 5 min) but remained high for more than 90 min. The level of damage achieved was dependent upon the ratio of neutrophils: target cells and was clearly detectable at ratios as low as 0.25:1. Induction of single-strand breaks was completely inhibited by catalase and partially inhibited by superoxide dismutase, mannitol, and reduced glutathione but not by Na azide. Addition of the non-steroidal anti-inflammatory drug indomethacin either enhanced (at 50 microM) or had no effect (at 2 microM) on the damage detected. Finally, repair of strand breaks induced by neutrophils was significantly slower (half-time approximately 10 min) than that observed for repair of similar levels of damage induced by H2O2 or gamma-irradiation (half-times approximately 3 min, each). The results indicate that neutrophils cause prolonged DNA damage in neighboring cells. Moreover, they indicate that although H2O2 produced in the oxidative burst is an essential mediator of the damage observed, additional reactive oxygen intermediates including the superoxide anion are also implicated. The data are discussed in relation to the possible role of neutrophils in chronic inflammation and in pristane-induced plasmacytoma formation in mice.
Carcinogenesis 1988 Dec
PMID:Activated neutrophils induce prolonged DNA damage in neighboring cells. 284 79

Male F-344 rats were fed a diet containing 2% di-(2-ethylhexyl)phthalate (DEHP) for 95 weeks. Liver nodules and/or hepatocellular carcinomas (HCC) developed in 6/10 rats fed DEHP and none were found in controls (P less than 0.005 by chi 2 test). All the nodules and HCC were negative for gamma-glutamyl transpeptidase. In the non-tumorous portions of liver, the hepatocytes contained an increased number of peroxisomes and extensive accumulation of lipofuscin. By immunocytochemical analysis, the liver peroxisomes in rats treated chronically with DEHP had visually detectable decrease in the H2O2-degrading catalase and increase in H2O2-producing fatty acyl-CoA oxidase. These results show that higher dietary level of DEHP, which causes substantially greater degree of peroxisome proliferation than the 1.2% dietary level used in the National Toxicology Program bioassay (1982, Publication no. NTP-80-37, Tech. Report Series No. 217), can induce liver tumors in male rats.
Carcinogenesis 1987 Sep
PMID:Absence of gamma-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. 288 2

Hepatic metabolism of long-chain fatty acids was studied in male rats fed a defined choline-deficient (CD) diet with and without choline and after methotrexate (MTX) administration. Peroxisomal beta-oxidation was increased approximately 4-fold in the peroxisome-enriched fraction of CD-fed animals, whereas the catalase activity was increased 1.3-fold. The urate oxidase activity was marginally affected. The CD-fed rats also revealed elevated capacity for hydrolysis of palmitoyl-CoA in the cytosolic fraction (2.0-fold), whereas the microsomal palmitoyl-CoA hydrolase activity was decreased. Notably, the increased peroxisomal beta-oxidation, the catalase activity and palmitoyl-CoA hydrolase activities (the membrane-bounded and cytosolic) were almost fully prevented by adding choline to the CD-diet. Thus, the change in these enzyme activities appears to be a consequence of a choline-deficiency provoked by the CD diet. MTX administration of normal fed rats (ND diet) had no effects on the peroxisomal beta-oxidation, catalase activity and urate oxidase activity. MTX treatment of the ND-fed animals, however, increased the mitochondrial palmitoyl-CoA hydrolase activity and decreased the microsomal enzyme activity. As choline-deficiency and MTX increased the hepatic lipid level, the overall results suggest that fat accumulation is not an 'induction signal' for increased peroxisomal beta-oxidation. The CD diet alone increased the reduced glutathione content in liver, whereas MTX did not significantly change this level. Whether the changes of H2O2-generating peroxisomal oxidation of long-chain fatty acids may be an important step in a chain of events, which eventually results in tumour formation by choline-deficiency, should be considered.
Carcinogenesis 1988 Apr
PMID:Effect of choline-deficiency and methotrexate administration on peroxisomal beta-oxidation, palmitoyl-CoA hydrolase activity and the glutathione content in rat liver. 289 92

Reduced glutathione (GSH) is mutagenic in Salmonella in the presence of gamma-glutamyltranspeptidase (GGT), with the highest response obtained in strain TA102. Reduced cysteinylglycine, one of the products of GGT metabolism of GSH, is mutagenic in the absence of GGT. In strain TA102, GSH mutagenesis was dependent on molecular oxygen, enhanced by iron, inhibited by EDTA, desferrioxamine mesylate, mannitol, butylated hydroxyanisole, peroxidase and catalase, but not by superoxide dismutase. Binding of GSH or its GGT-dependent metabolites to DNA in vitro was not detected. This is consistent with a model of an indirect mechanism of mutagenesis, i.e. cleavage of GSH by GGT, followed by facile auto-oxidation of the resulting cysteinylglycine, with the production of free radicals which lead to the (pen)ultimate mutagen, H2O2.
Carcinogenesis 1988 May
PMID:Glutathione mutagenesis in Salmonella typhimurium is a gamma-glutamyltranspeptidase-enhanced process involving active oxygen species. 289 53


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