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

The carcinogenic potency of simple aliphatic alkylating agents such as the alkylnitrosamides and the alkylmethanesulphonates is positively correlated with their ability to alkylate the relatively weakly nucleophilic oxygen atoms in DNA, particularly the O6-atom of guanine. Differences in the spectrum of DNA alkylations produced by these agents can be rationalised on chemical grounds in that the electrophilic reactivity of the alkylating species determines the extent to which it will react at sites of weaker nucleophilicity. Alkylation of the more strongly nucleophilic ring nitrogen atoms of the purine bases, which is the main site of reaction with all these agents, appears to be much less important in alkylation carcinogenesis. O6-alkylation of guanine is likely to interfere with DNA base-pair hydrogen bonding and is possibly the major DNA modification responsible for the induction of GC yields AT transition mutations in bacteria and bacteriophage by alkylating agents. Here, we have studied the effects of three methylating agents of contrasting carcinogenic potency on mammalian (V79 Chinese hamster) cells in in culture. We report that the mutagenicity but not the cytotoxicity of each agent reflects its carcinogenicity and, furthermore, that the marked differences in mutagenicity are closely paralleled by differences in levels of O6-guanine methylation.
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PMID:Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification. 735 43

Epidemiologic evidence suggests that cigarette smoking is a major risk factor for chronic obstructive pulmonary diseases such as chronic bronchitis and emphysema, for carcinogenesis, and for cardiovascular disease. However, the precise mechanisms of these effects are incompletely understood. The gas phase of cigarette smoke contains abundant free radicals including nitric oxide. Hence, cigarette smoke may induce some of its damaging effects by free radical mechanisms. We report that exposure of plasma, a model for respiratory tract lining fluids, to gas-phase cigarette smoke causes depletion of antioxidants, including ascorbate, urate, ubiquinol-10, and alpha-tocopherol, and a variety of carotenoids, including beta-carotene. Gas-phase cigarette smoke induced some lipid peroxidation, as measured by cholesteryl linoleate hydroperoxide (18:2OOH) formation. Ascorbate was effective in preventing 18:2OOH formation. In contrast to the low concentrations of lipid hydroperoxides measured (< 1 mumol/L), protein carbonyl formation, a measure of protein modification, increased by approximately 400 mumol/L after nine puffs of cigarette smoke. Reduced glutathione inhibited protein carbonyl formation, whereas other plasma antioxidants, including ascorbate, were ineffective. alpha, beta-Unsaturated aldehydes (acrolein and crotonaldehyde) in cigarette smoke may react with protein -SH and -NH2 groups by a Michael addition reaction that results in a protein-bound aldehyde functional group. Gas-phase cigarette smoke is capable of converting tyrosine to 3-nitrotyrosine and dityrosine, indicating free radical mechanisms of protein damage by nitrogen oxides. Aldehydes and nitrogen oxides in cigarette smoke may be significant contributors to biomolecular damage, and endogenous antioxidants can attenuate some of these adverse effects.
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PMID:Dietary antioxidants and cigarette smoke-induced biomolecular damage: a complex interaction. 749 50

L-Arginine-derived nitric oxide (NO) and its derivatives, such as peroxynitrite and nitrogen dioxide, play a role in inflammation and also possibly in the multistage process of carcinogenesis. We investigated the effect of various non-steroidal anti-inflammatory agents and related compounds on the induction of NO synthase (NOS) in RAW 264.7 macrophages activated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Low concentrations of curcumin, a potent anti-tumour agent having anti-inflammatory and anti-oxidant properties, inhibited NO production, as measured by the amount of nitrite released into the culture medium in 24 h (IC50 = 6 microM). NOS activity in soluble extracts of macrophages activated for 6-24 h in the presence of curcumin (10 microM) was significantly lower than that of macrophages activated without curcumin. Northern-blot and immunoblotting analyses demonstrated that significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in macrophages activated with curcumin, compared to those without curcumin. Inhibition of NOS induction was maximal when curcumin was added together with LPS and IFN-gamma and decreased progressively as the interval between curcumin and LPS/IFN-gamma was increased to 18 h.
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PMID:Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. 753 2

The potential role of antioxidant vitamins (ascorbic acid, beta-carotene, alpha-tocopherol), minerals (selenium) and non-vitamin natural antioxidants (e.g. glutathione) in the prevention of cancer diseases is reviewed. Free oxygen radicals, especially the hydroxyl radical .OH modify nitrogen bases, split DNA, stimulate oncogene activators and probably in many other ways participate in carcinogenesis. In a great number of experimental and epidemiological studies a significant increase of cancer risk in laboratory animals and in humans with low antioxidant status was found. Significant protective effects of ascorbic acid, beta-carotene, alpha-tocopherol and selenium against the incidence of gastrointestinal and lung cancer were achieved in most, but not in all prospective and intervention studies. It is probable that extremely high premature cancer mortality in postcommunist countries of Central and East Europe is caused by high consumption of cigarettes, spirits and saturated fats, by pollution, and by very low consumption of the chief sources of natural antioxidants (fruits, vegetables). (Fig. 13, Ref. 29).
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PMID:[The role of antioxidants in the prevention of tumors]. 755 84

Nitric oxide and superoxide anion, both formed in inflamed tissues, react rapidly to form the peroxynitrite anion (ONOO-), a strong oxidant which can initiate reactions characteristic of hydroxyl radical (HO.), nitronium ion (NO2+) and nitrogen dioxide radical (NO2.). Peroxynitrite, therefore, may cause DNA or tissue damage, contributing to the multistage carcinogenesis process. We have studied reactions of various bases, nucleosides or deoxynucleosides with peroxynitrite in vitro. Guanine reacted rapidly with peroxynitrite under physiological conditions and formed several substances, two of which were yellow, a characteristic of nitro and nitroso compounds. On the basis of chromatographic and spectral evidence we identified the major compound (which accounts for approximately 80% of all compounds formed) as 8-nitroguanine. Its formation was maximal at approximately pH 8 and increased dose-dependently with peroxynitrite concentration, but was not dependent on guanine concentration. The presence of ferric ions, which has been shown to catalyse nitration of tyrosine, did not affect nitration of guanine. 8-Nitroguanine could act as a specific marker for DNA damage induced by peroxynitrite in inflamed tissues.
Carcinogenesis 1995 Sep
PMID:Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. 755 52

Urinary excretions of nitrate and N-nitrosothiazolidine-4-carboxylic acid (N-nitrosothioproline; NTPRO) were determined in rats with osteogenic disordered syndrome (ODS, od/od), lacking L-ascorbic acid (ASC) biosynthesis, after i.p. administration of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg) followed by thiazolidine-4-carboxylic acid (thioproline, 20 mg/rat). L-Ascorbic acid-sufficient ODS rats showed the excretion of nitrate and NTPRO at the levels of 20.3 +/- 7.9 mumol/24h and 369 +/- 111 pmol/24 h respectively, whereas the levels of nitrate and NTPRO in ASC-deficient (scorbutic) rats increased to 54.7 +/- 5.6 mumol/24 h (P < 0.01) and 796 +/- 367 pmol/24 h (P < 0.05) respectively. Administration of L-arginine further increased urinary excretion of nitrate and NTPRO while D-arginine showed no effect. NG-Monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase (NOS), strongly inhibited endogenous formation of both nitrate and NTPRO. These results indicate that increased excretion of NTPRO in ODS rats stimulated by LPS involves induction of NOS leading to an increase in endogenous formation of reactive nitrogen oxides such as N2O3, a potent nitrosating agent at physiological pH conditions. Increased NOS activities in the plasma and various tissues of ODS rats were observed 5 h after treatment with LPS. The possibility of extragastric N-nitroso compound formation in inflammation sites is discussed.
Carcinogenesis 1995 Nov
PMID:Marked increase in urinary excretion of nitrate and N-nitrosothioproline in the osteogenic disordered syndrome rats, lacking ascorbic acid biosynthesis, by administration of lipopolysaccharide and thioproline. 758 82

Pyrrolizidine alkaloids (PAs) are potent carcinogenic and anti-mitotic compounds produced by a large number of plant species. In this study, we investigated in vitro the DNA-protein cross-linking activity of several structurally diverse PAs. The DNA cross-linked proteins induced by PAs were also isolated and characterized in mammalian cells. At 300 and 500 microM, the pyrrolic PAs (dehydrosenecionine, dehydromonocrotaline, dehydroseneciphylline, dehydroriddelliine) induced potent DNA cross-links. Protein-associated DNA cross-links accounted for approximately 50% of the total cellular DNA cross-links at 300 microM. The simple necine pyrrole dehydroretronecine induced few DNA--protein cross-links and none were detected with indicine N-oxide. The major proteins cross-linked to DNA from either PA-exposed cells or pyrrolic PA-exposed nuclei were in the molecular weight 40-60 kDa range and were primarily acidic in nature (Ca. pI 4.2-5.0). The patterns of the proteins cross-linked to DNA were similar to that induced by standard bifunctional alkylating agents mitomycin C, cisdichlorodiammine platinum(II) and nitrogen mustard. The macrocyclic pyrrole dehydrosenecionine induced DNA cross-links in pBR322 plasmid DNA with BSA as a protein target. Our data indicated that pyrrolic PAs with a macrocyclic diester such as dehydrosenecionine, dehydroseneciphylline, dehydroriddelliine and dehydromonocrotaline were more potent cross-linkers than the simple necine pyrrolic dehydroretronecine. Cross-linking potency of the PAs examined here coincides with known potency differences in animal toxicity and led us to conclude that DNA--protein cross-linking activity is probably involved in PA-related
Carcinogenesis 1995 Nov
PMID:Pyrrolizidine alkaloid-induced DNA-protein cross-links. 758 88

The endogenous production of nitric oxide (NO) and its role in the neoplastic transformation of C3H 10T1/2 mouse fibroblasts were investigated. NO production, as indicated by NO2- in the culture medium, was increased in cells initiated with 3-methylcholanthrene or stimulated with the combination of interferon-gamma (IFN gamma, 10 ng/ml) plus bacterial lipopolysaccharide (LPS, 1 micrograms/ml). NO2- was detectable within 24-48 h of IFN gamma/LPS treatment and accumulated to micromolar concentrations within 4 days. NO production was inhibited in a dose-dependent manner by analogs of L-arginine in which the terminal guanidino nitrogen is blocked, consistent with NO production by the oxidative deamination of L-arginine by nitric oxide synthase (NOS). IFN gamma/LPS-stimulated cells expressed a 4.4 kb mRNA which hybridized to a probe for the mouse macrophage-inducible NOS. Expression of the rat cerebellar constitutive NOS was not detected in these cells. Arginine analogs added to the culture medium during the post-confluence promotional stages of the C3H 10T1/2 transformation assay blocked the formation of transformed foci in a dose-dependent manner comparable to their inhibition of NO production. These data demonstrate that C3H 10T1/2 mouse fibroblasts are a useful model for the study of the effects of endogenous NO production in carcinogenesis and suggest that NO plays a significant role in the promotional phase of neoplastic transformation of these cells.
Carcinogenesis 1993 Aug
PMID:Inhibitors of endogenous nitrogen oxide formation block the promotion of neoplastic transformation in C3H 10T1/2 fibroblasts. 768 37

To study the impact of DNA nucleotide excision repair (NER) on the spectrum of mutations induced by alkylating agents, postmeiotic male germ cell stages of Drosophila melanogaster were exposed to methyl methanesulfonate (MMS) and the males then mated with nucleotide excision repair deficient (exr-; mus(2)201) females. MMS (s value = 0.86) has a strong preference for alkylating the nitrogen positions in DNA, whereas < 1% of all DNA lesions are on oxygen. For genetic and molecular analysis of the types of mutations induced by MMS the vermilion locus was used as target gene. Mutation induction by MMS was increased 10-fold under the exr- conditions compared to a normal functioning repair system. The genetic analysis showed that < 15% of the mutants represented inter-locus mutations, which were classified as multi-locus deletions. Of the intra-locus mutations (18 F1 and 8 F2 mutants) 78% were transversions with a clear dominance of AT-->TA (11 in the F1, 3 in the F2) and few GC-->TA (2 in the F1, 3 in the F2) type of transversions. In comparison to the MMS spectrum produced under repair proficient (exr+) condition (Nivard, M.J.M., Pastink, A. and Vogel, E.W., 1992), the exr- spectrum shows a significant decrease in the percentage of deletions and a relative increase in transversions. These data are consistent with previously published papers suggesting that under normal repair conditions the nitrogen DNA adducts are efficiently repaired in Drosophila and that the hypermutability of MMS in the exr- strain is caused by an increased formation of apurinic sites either formed from 3-methyladenine or 7-methylguanine. This suggests that also in Drosophila 'the A-rule' is valid, indicating that during DNA replication an adenine (A) is preferentially incorporated opposite to non-instructive apurinic sites.
Carcinogenesis 1993 Aug
PMID:Impact of DNA nucleotide excision repair on methyl methanesulfonate-induced mutations in Drosophila melanogaster. 768 38

Male CD-1 mice were exposed to an nominal concentration of 20 p.p.m. of 15N-nitrogen dioxide (15NO2) for 6 h/day for 4 days and for 2 h on the day 5, and to 1 g morpholine/kg body wt by gavage daily for five consecutive days. N-Nitrosomorpholine (NMOR) was found in whole mice, stomachs, skins with hair, and remains. The sum of individual tissue concentrations measured separately was 3421 ng/tissue, where the average skin weighed 4.3 g, the average stomach weighed 1.0 g and the average remains weighed 22.2 g. The average whole mouse weighed 27.7 g and contained a total of 3903 ng of NMOR. The concentration of NMOR was highest in the skin, next highest in the stomach, and lowest in the remains. However, the total quantity of NMOR per tissue, while highest in the skin (83%), was next highest in the remains (14.8%) and lowest in the stomach (2.2%). GC-MS analysis served to distinguish between the NMOR of 15NO2 origin and that of other origin. All of the NMOR in the whole mouse homogenates was identified as 15NMOR. In the stomach 73% was identified as 14NMOR, representing 1.6% of the total NMOR in the mouse, and 27% as 15NMOR, representing 0.6% of the total NMOR in the mouse. N-Nitrosamine formation in vivo is discussed as a possibly ongoing mammalian process.
Carcinogenesis 1995 Jan
PMID:Endogenous formation of N-nitrosomorpholine in mice from 15NO2 by inhalation and morpholine by gavage. 783 9


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