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

Chemoprevention by a synthetic retinoid, selenium, and these agents in combination during the postinitiation stages of carcinogenesis induced in rats by azaserine was evaluated. Male Lewis rats were given three weekly injections of 30 mg/kg azaserine while being fed a purified diet. One week after completion of carcinogen treatment, groups of rats were switched to the purified diet supplemented with either a retinoid, N-(2-hydroxyethyl)retinamide, at a level of 0.5 or 1 mmol/kg diet, or with 5 ppm sodium selenite, or with a combination of retinoid and selenium. One year after the diet change, the incidence of pancreatic and other neoplasms was determined by autopsy and histologic study. The incidence of pancreatic carcinoma (including carcinoma-in-situ, CIS) among nonretinoid-treated controls was 68%. Since the dietary supplements were fed after completion of exposure to the carcinogen, the effects on both pancreatic and liver carcinogenesis were exerted during the postinitiation phase of carcinogenesis. As in previous studies, the retinoid inhibited the progression of pancreatic carcinogenesis in a dose-related fashion. Selenium alone had no effect. However, the combination of retinoid plus selenium was more effective than retinoid alone, although the increase in inhibition was not large. The retinoid was also found to inhibit liver carcinogenesis induced by azaserine. Selenium, either alone or in combination with retinoid, was ineffective. Finally, testicular atrophy, noted as a toxic effect of retinoids in other studies, was not observed in this work.
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PMID:Inhibition of pancreatic and liver carcinogenesis in rats by retinoid- and selenium-supplemented diets. 325 90

Rabbit antibodies against O6-(2-hydroxyethyl)-2'-deoxyguanosine (O6-HEdg) were used to develop a highly sensitive immuno-slot-blot assay for this promutagenic base which enabled the quantitation of greater than or equal to 3.6 mumol O6-HEdG/mol deoxyguanosine, corresponding to greater than or equal to 5 fmol in a 3-mug DNA sample. This assay was used to study DNA hydroxyethylation by N-nitroso-N-(2-hydroxyethyl)urea (HENU) in adult male F344 rats. Initial amounts of O6-HEdG 2 h after a single i.v. dose of 50 mg/kg were highest in kidney (81 mumol O6-HEdG/mol deoxyguanosine), followed by lung and liver (67 and 55 mumol/mol dG respectively). Formation of O6-HEdG in cerebral DNA was considerably lower (18 mumol O6-HEdG/mol deoxyguanosine), probably reflecting delayed crossing of the blood-brain barrier by HENU due to its hydrophilicity. The formation of O6-HEdG in liver and kidney was strictly proportional to dose over a range of 5-50 mg HENU/kg. Repair of O6-HEdG was very rapid in liver (apparent half-life, 12 h), and somewhat slower in kidney and lung (approximate half-life, 40 h and 48 h respectively). In contrast, 62% of the initial amount of O6-HEdG in cerebral DNA was still present after 7 days. Saturation of the hepatic O6-alkyl-guanine-DNA alkyltransferase by pretreatment with N-nitroso-dimethylamine (20 mg/kg) almost completely inhibited the removal of O6-HEdG, indicating that O6-HEdG is predominantly repaired by this repair enzyme.
Carcinogenesis 1988 Jan
PMID:Formation and persistence of O6-(2-hydroxyethyl)-2' -deoxyguanosine in DNA of various rat tissues following a single dose of N-nitroso-N-(2-hydroxyethyl)urea. An immuno-slot-blot study. 327 2

Directly-acting mutagens formed from N-nitroso-N-(formylmethyl)alkylamines (I) were isolated and identified as N-nitroso-N-alkyl-1-hydroxyimino-2-oxoethylamines (II). Their structures were elucidated on the basis of nuclear magnetic resonance spectra and confirmed by leading to their crystalline 2,4-dinitrophenylhydrazone. II (alkyl = ethyl and n-butyl) were strongly mutagenic to Salmonella typhimurium TA1535 and Escherichia coli WP2 hcr- without metabolic activation, while II with a tert-butyl group was not mutagenic. The formation of II from I is considered to proceed by the nitrosation of I, indicating a possible involvement of a formylmethyl metabolite in the carcinogenesis of nitrosamines with a 2-hydroxyethyl group.
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PMID:Directly-acting mutagens formed from N-nitroso-N-(formylmethyl)alkylamines. 331 95

Metronidazole, which is known to react with DNA under certain conditions, forms an adduct with guanosine in the presence of the reducing agent, sodium dithionite. This product has been purified by HPLC, characterized by UV and fast atom bombardment mass spectrometry, and tentatively identified as 1-(2-hydroxyethyl)-2-methyl-5-(N2-guanosinylamino)imidazole. This adduct is very unstable and decomposes to a variety of products including guanosine. Formation of this and similar DNA adducts from metronidazole in vivo, and the decomposition of these products, are probably both strongly dependent on details of intracellular metabolism.
Carcinogenesis 1988 Apr
PMID:Reaction of reduced metronidazole with guanosine to form an unstable adduct. 335 67

The metabolism of N-nitrosodiethanolamine (NDELA) was studied to assess whether the formation of the beta-oxidized metabolites, N-nitroso(2-hydroxyethyl) (formylmethyl)amine (NHEFMA) and N-nitroso(2-hydroxyethyl)(carboxymethyl)amine (NHECMA), is involved in tumour induction in various animal species with different susceptibilities to NDELA carcinogenicity. In-vitro and in-vivo studies showed that all the animal species considered metabolize NDELA through the beta-oxidation pathway, suggesting that there is no correlation between carcinogenesis by NDELA and its beta-oxidation.
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PMID:Beta-oxidation of N-nitrosodiethanolamine in different animal species in vitro and in vivo. 367 47

Globin samples from ethylene oxide-exposed workers and non-exposed referrents were analysed by two methods: (i) gas chromatography-mass spectrometry determination of Nt-(2-hydroxyethyl)histidine as its methyl ester heptafluorobutyryl derivative, after hydrolysis of the protein and isolation of the alkylated amino acid by ion exchange chromatography. The internal standard, Nt-(2-hydroxy-d4-ethyl)histidine, was added to the protein before hydrolysis. (ii) Determination of N-(2-hydroxyethyl)valine after derivatization of the protein by a modified Edman procedure, extraction and g.c.-m.s. determination of alkylated N-terminal valine in the form of its pentafluorophenylthiohydantoin derivative. The internal standard used was in this case a globin with a known content of hydroxy-d4-ethylated amino acids. The two methods gave consistent results, especially at high levels of alkylated products. The average content of hydroxyethylhistidine was 0.6 nmol/g higher than the content of hydroxyethylvaline. Higher levels of background alkylation (of unknown origin) were recorded with the histidine method as compared with the valine method, suggesting that the latter assay should show greater sensitivity for low level ethylene oxide exposure monitoring.
Carcinogenesis 1986 Apr
PMID:Monitoring human exposure to ethylene oxide by the determination of haemoglobin adducts using gas chromatography-mass spectrometry. 369 96

The metabolism of N-nitrosodiethanolamine (NDELA) was studied to assess whether the formation of the beta-oxidated metabolites N-(2-hydroxyethyl)-N-(formylmethyl)nitrosamine (EFMN) and N-(2-hydroxyethyl)-N-(carboxymethyl)nitrosamine (ECMN) is involved in the mechanism of tumor induction in various animal species with different susceptibility to NDELA carcinogenicity. In vitro studies using liver S9 fractions from rats, hamster, B6C3F1 and CD-1 mice and rabbits showed that all the animal species metabolize NDELA through the beta-oxidation pathway, although to different extents. Urinary excretion of NDELA and its metabolite ECMN in rats, hamsters and mice after 5 mg X kg-1 NDELA i.p. confirmed these findings. The results suggest there is no correlation between carcinogenesis by NDELA and its beta-oxidation. The possibility that ECMN formation might represent a detoxifying metabolic pathway for NDELA is discussed.
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PMID:Comparative in vitro and in vivo beta-oxidation of N-nitrosodiethanolamine in different animal species. 376 52

DNA substrates containing O6-n-butylguanine, O6-iso-butylguanine, O6-n-propylguanine and O6-iso-propylguanine were prepared by reaction of calf thymus DNA with the appropriate N-alkyl-N-nitrosourea. These substrates were used to test the ability of O6-alkylguanine-DNA alkyltransferases from Escherichia coli and rat liver to remove such alkyl groups from the O6-position of guanine. It was found that all of these adducts were removed by the alkyltransferases, but the branched alkyl chain iso-butyl- and iso-propyl adducts were removed very slowly. Also, when tested with a DNA substrate containing both O6-n-propylguanine and O6-iso-propylguanine, the alkyltransferases removed almost all of the n-propyl-adduct before the iso-propyl-adduct was attacked. Both alkyltransferases showed a decreasing rate of reaction as the size of the alkyl group increased, but there was a significant difference between the rat liver and E. coli alkyltransferase in the relative rates. The rat liver alkyltransferase repaired O6-methylguanine more slowly than the E. coli protein, but was considerably more rapid than the bacterial equivalent when acting on n-propyl- and n-butyl-adducts. The relative rates of repair were methyl much greater than ethyl greater than n-propyl greater than n-butyl greater than iso-propyl, iso-butyl for the E. coli alkyl-transferase and methyl greater than ethyl, n-propyl greater than n-butyl greater than iso-propyl, iso-butyl greater than 2-hydroxyethyl for the rat liver protein. These results indicate that differential rates of repair may contribute to the relative risks of carcinogenesis and mutagenesis by exposure to alkylating agents of different size and that rates of repair may be species specific and must be determined from specific measurements rather than extrapolated from data on other organisms.
Carcinogenesis 1985 Jul
PMID:Repair of O6-propylguanine and O6-butylguanine in DNA by O6-alkylguanine-DNA alkyltransferases from rat liver and E. coli. 389 82

The two isomeric N-nitroso derivatives of the dialkylurea, 1-ethyl-3-(2-hydroxyethyl)urea, were given by gavage to 20 male F344 rats for 30 weeks at equimolar doses. The tumorigenic responses were compared with those to a similar dose of nitrosoethylurea or nitroso-2-hydroxyethylurea. Each of the nitrosomonoalkylureas caused death from tumors more rapidly than the analogous nitrosodialkylurea. Each of the nitrosodialkylureas induced a broader spectrum of tumors in the rats than did either nitrosoethylurea or nitroso-2-hydroxyethylurea, including neoplasms of the thyroid, lung, skin, colon, mesotheliomas and neoplasms of the brain and liver in high incidence, the last two of which were not seen in animals given the nitrosomonoalkylureas. On the other hand, there were fewer tumors of the forestomach in rats given the nitrosodialkylureas than with the nitrosomonoalkylureas. The major difference between 1-nitroso-1-ethyl-3-hydroxyethylurea and 1-nitroso-1-hydroxyethyl-3-ethylurea was that the former induced only neoplastic nodules in the liver of 30% of the rats, while the latter induced hepatocellular carcinomas in 55% of the rats; approximately half of the rats given either compound had brain neoplasms, which included astrocytomas, gliomas and oligodendrogliomas.
Carcinogenesis 1985 Apr
PMID:Similar carcinogenic effects in rats of 1-ethyl-1-nitroso-3-hydroxyethylurea and 1-hydroxyethyl-1-nitroso-3-ethylurea. 398 67

(Hydroxyalkyl)nitrosoureas and the related cyclic carbamates N-nitrosooxazolidones are potent carcinogens. The decompositions of four such compounds, 1-nitroso-1-(2-hydroxyethyl)urea (I), 3-nitrosooxazolid-2-one (II), 1-nitroso-1-(2-hydroxypropyl)urea (III), and 5-methyl-3-nitrosooxazolid-2-one (IV), in aqueous buffers at physiological pH were studied to determine if any obvious differences in decomposition pathways could account for the variety of tumors obtained from these four compounds. The products predicted by the literature mechanisms for nitrosourea and nitrosooxazolidone decompositions (which were derived from experiments at pH 10-12) were indeed the products formed, including glycols, active carbonyl compounds, epoxides, and, from the oxazolidones, cyclic carbonates. Furthermore, it was shown that in pH 6.4-7.4 buffer epoxides were stable reaction products. However, in the presence of hepatocytes, most of the epoxide was converted to glycol. The analytical methods developed were then applied to the analysis of the decomposition products of some related dialkylnitrosoureas, and similar results were obtained. The formation of chemically reactive secondary products and the possible relevance of these results to carcinogenesis studies are discussed.
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PMID:Decomposition reactions of (hydroxyalkyl) nitrosoureas and related compounds: possible relationship to carcinogenicity. 402 Aug 29


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