Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifteen specific inhibitors of DNA topoisomerases I and II were used to elucidate whether these enzymes participate in the excision repair of UV-induced DNA damage, monitoring DNA repair synthesis in confluent saponin-permeabilized human fibroblasts. To achieve a sufficient degree of accuracy dose--response experiments were performed, analysed by linear regression, and the concentrations at which repair activity was reduced to 50% were calculated and designated K50. Camptothecin, a specific inhibitor of topoisomerase I did not markedly diminish DNA repair synthesis. Similarly, when combined with topoisomerase II inhibitors [nalidixic acid, oxolinic acid, 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside) (etoposide), 4'-demethylepipodophyllotoxin-thenylidene-beta-D-glucoside (teniposide), 1,4-dihydroxy-5,8-bis ((2-[(2-hydroxyethyl)amino]ethyl)amino)-9,10-anthracenedione (mitoxantrone), 5-(N-phenyl-carboxamido)-2-thiobarbituric acid (merbarone) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)], it did not lower K50 values determined for topoisomerase II-specific drugs in separate experiments. The effects observed can be classified according to the mechanism of action the inhibitors exhibit. (i) Novobiocin and coumermycin, inhibitors of the ATPase subunit of topoisomerase II, completely reduced DNA repair synthesis. (ii) Inhibition of repair was also found for ethidium bromide, quinacrine and distamycin, drugs known to modify the DNA substrate by intercalation or binding to the DNA minor groove. (iii) Inhibitors acting through intercalation and, simultaneously, binding to the cleavable DNA-topoisomerase complex (m-AMSA, mitoxantrone, doxorubicin and daunorubicin) also suppressed reparative DNA synthesis. (iv) Only small effects were observed for etoposide, nalidixic acid and oxolinic acid, whereas teniposide caused marked inhibition of DNA repair synthesis. (v) Merbarone, a novel type of topoisomerase II inhibitor, blocked UV-induced DNA repair drastically. The results are best explained by assuming that in UV-irradiated human fibroblasts the 180 kDa form of topoisomerase II is the main target enzyme for inhibitors which suppressed DNA excision repair and that this isozyme is involved in steps preceding repair-specific DNA incision.
Carcinogenesis 1992 Dec
PMID:The function of DNA topoisomerases in UV-induced DNA excision repair: studies with specific inhibitors in permeabilized human fibroblasts. 133 77

Hemoglobin (Hb) adduct determination by the N-alkyl Edman method was used for in vivo dosimetry of endogenously formed malonaldehyde (MA) and ethene in mice fed diets with different fatty acid composition and induced for lipid peroxidation with carbon tetrachloride (CCl4). In order to amplify lipid peroxidation animals were pretreated with phenobarbital (PB) and the glutathione-depleting agent DL-buthionine-(S,R)-sulfoximine (BSO). Non-treated animals raised on different diets were used as controls. Lipid peroxidation products in liver were measured as 2-thiobarbituric acid reactive compounds (TBA-C). Livers from control mice fed a soya oil based diet (rich in polyunsaturated fatty acids, diet S) showed approximately 6.5-fold higher levels of TBA-C than those from animals raised on a coconut oil based diet (mostly saturated fatty acids, diet C). The level of adducts of MA to Hb, determined as N-(3-hydroxypropyl)valine, was approximately 1.5-fold higher in animals from diet S than in animals raised on diet C. The highest increases in the levels of TBA-C and MA adducts were obtained after a simultaneous treatment of the animals with PB, BSO and CCl4. The increases of TBA-C were 1.3-fold (diet C) and 1.7-fold (diet S). The corresponding increases of MA-Hb adduct levels were 1.3- and 1.6-fold respectively, indicating an increased susceptibility of mice fed diet S to lipid peroxidation. The level of adducts from ethene, determined as N-(2-hydroxyethyl)valine, was also higher in mice from diet S than in animals fed diet C, when all treatment groups were considered. The difference was, however, only slightly significant (P less than 0.02). No difference between control and CCl4-treated animals, with regard to the ethene-Hb adduct, was found. Our results validate the use of Hb dosimetry for monitoring the effects of factors known to influence lipid peroxidation induced in vivo.
Carcinogenesis 1991 Jun
PMID:In vivo hemoglobin dosimetry of malonaldehyde and ethene in mice after induction of lipid peroxidation. Effects of membrane lipid fatty acid composition. 167 Feb 88

The endogenous formation of nitrate in the rat, mouse and human occurs through cellular processes involving the oxidation of the guanido group of arginine. These processes proceed from arginine to nitric oxide with subsequent conversion to electrophilic nitrosating agents capable of forming carcinogenic nitrosamines. We have now demonstrated that endogenous nitrosamine formation can occur via cells stimulated in vivo by bacterial lipopolysaccharide (LPS). The nitrosation of morpholine given to rats by i.p. injection yields N-nitrosomorpholine (NMOR) which is subsequently oxidized in the liver. A major metabolite of NMOR, N-nitroso-(2-hydroxyethyl)glycine, was previously shown by other investigators to be excreted into urine. Treatment of rats with LPS, arginine and morpholine creates a large increase in NMOR urinary metabolites over a 24-h period. This process is not influenced by simultaneous dosage with large amounts of NaNO3. Therefore the endogenous LPS-induced formation of NMOR proceeds directly from nitric oxide prior to incorporation into the nitrate body pool. The proportion of endogenously synthesized nitric oxide incorporated into NMOR is approximately 3 x 10(-6).
Carcinogenesis 1991 Mar
PMID:Endogenous incorporation of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by Escherichia coli lipopolysaccharide in the rat. 184 54

Antihelmintic treatment with piperazine (1,4-diazacyclohexane) for microfilarie parasitism results in the endogenous formation of piperazine-derived N-nitrosamines. The urinary excretion of these N-nitrosamines was determined by biochemical monitoring of 14 patients receiving 2 g piperazine citrate. The urinary excretion (mean +/- SD) of N-mononitrosopiperazine (MNPz) was 27.0 +/- 26.7 micrograms/day (range 0.6-96.0 micrograms/day). Trace levels of 0.73 +/- 0.92 micrograms/day N,N'-dinitrosopiperazine (DNPz) (range ND-2.8 micrograms/day) were also found in 7 of 14 urine samples. N-Nitroso-3-hydroxypyrrolidine (NHPYR), a metabolite of both MNPz and DNPz, was detected in 11 of 14 urine samples at a mean concentration of 1.74 +/- 1.72 micrograms/day (range ND-5.7 micrograms/day) and traces of N-nitrosodiethanolamine in two samples at levels of 0.3 and less than 0.1 micrograms/day. The results show that biochemical monitoring of urinary NHPYR may be a good indicator of endogenous MNPz formation. While DNPz was also detected in urine, conclusive validation for its endogenous formation could not be provided because no evidence was found for the presence of its major metabolite, N-nitroso-(2-hydroxyethyl)glycine in urine.
Carcinogenesis 1991 Sep
PMID:Endogenous formation of N-nitrosamines from piperazine and their urinary excretion following antihelmintic treatment with piperazine citrate. 189 19

The role of bacteria in catalysing intragastric formation of N-nitrosothiazolidine-4-carboxylic acid and N-nitrosomorpholine was investigated in a rat model of omeprazole-induced achlorhydria. Omeprazole-treated rats gavaged with nitrosation-proficient bacteria were treated with nitrosamines and/or precursors and compared to control animals that received no omeprazole treatment/no bacteria. Rats given thiazolidine-4-carboxylic acid, nitrate and 10(11) cells of Escherichia coli, had a five times higher endogenous formation of N-nitrosothiazolidine-4-carboxylic acid as compared to controls. Endogenous formation of N-nitrosomorpholine was quantified by measuring its urinary metabolite N-nitroso-(2-hydroxyethyl)glycine; when rats were given morpholine and nitrite together with E. coli or Pseudomonas aeruginosa endogenous N-nitrosomorpholine formation was increased approximately 2.5-fold as compared to controls. In the same experiment, a higher excretion of unchanged N-nitrosomorpholine was also observed in omeprazole-treated rats receiving bacteria as compared to controls. Rats given morpholine, nitrate and E. coli or P. aeruginosa, excreted three times higher levels of N-nitrosomorpholine as compared to controls. These results conclusively demonstrate that nitrosation-proficient bacteria are capable of increasing intragastric formation of N-nitrosothiazolidine-4-carboxylic acid and N-nitrosomorpholine. These N-nitrosamines are formed from nitrate (or nitrite) and the respective amino precursor via reduction of nitrate into nitrite and bacterial nitrosation catalysis.
Carcinogenesis 1991 Mar
PMID:Bacterial formation of N-nitroso compounds from administered precursors in the rat stomach after omeprazole-induced achlorhydria. 190 Dec 50

Monoclonal antibodies have been obtained against imidazole ring-opened N7-ethylguanine (RON7-EtGua) in DNA. The antibodies were selected for good performance in the ELISA with either DNA or nucleated blood cells as immobilized antigen. Antibodies thus selected were studied for their suitability for the in situ detection of RON7-EtGua in the nuclei of cells by means of immunofluorescence microscopy (IFM). Two antibodies have been characterized in detail with respect to specificity and sensitivity. Competitive ELISA demonstrated that the antibodies recognize not only RON7-EtGua but also the corresponding methyl and 2-hydroxyethyl components, with efficiencies that vary with the chemical environment (base, nucleoside or DNA), the nature of the alkyl group and the antibody. They have a clear specificity for the ring-opened alkyl adducts and show an at least 100-fold stronger preference for such structures in DNA when compared to the free nucleoside adducts. Furthermore, they hardly bind to non-alkylated DNA, and do not bind to guanosine or N1- or O6-ethylguanosine. Analysis by DNA-ELISA showed that the binding preference of antibody N7E-026 for ring-opened alkyl adducts is methyl approximately ethyl greater than 2-hydroxyethyl much greater than sulphur mustard, while that of N7E-102 is 2-hydroxyethyl greater than ethyl greater than methyl approximately sulphur mustard. Analysis of RON7-EtGua in DNA with competitive ELISA, DNA-ELISA and IFM showed that in all cases the lowest detection limit can be reached with antibody N7E-026. Competitive ELISA was the most sensitive method, followed by DNA-ELISA and IFM, with detection limits of 2.2, 16 and 23 RON7-EtGua/10(6) nucleotides respectively. In the DNA-ELISA, 12 methyl adducts/10(6) nucleotides can be detected with N7E-026 and 11 2-hydroxyethyl adducts/10(6) nucleotides with N7E-102.
Carcinogenesis 1991 Jun
PMID:The isolation of monoclonal antibodies selected for the detection of imidazole ring-opened N7-ethylguanine in purified DNA and in cells in situ. Crossreaction with methyl, 2-hydroxyethyl and sulphur mustard adducts. 204 82

Reaction products with DNA and blood proteins have been used for monitoring human exposure to electrophilic compounds and metabolites. The formation of products with nucleophilic sites in DNA after treatment with such reagents has been well characterized (especially for alkylating agents). It is therefore of great importance to collect corresponding data for nucleophilic groups in proteins. The formation of reaction products in hemoglobin (Hb) and DNA was studied after in vitro treatment with ethylene oxide (EtO) and N-(2-hydroxyethyl)-N-nitrosourea (HOEtNU). In DNA N-7-(2-hydroxyethyl)guanine was the main product of EtO, whereas O6-(2-hydroxyethyl)guanine was much lower (0.5% of the alkylation of guanine-N-7). For HOEtNU O6-(2-hydroxyethyl)guanine was found to be 63% of N-7-(2-hydroxyethyl)guanine. These relative reactivities are in agreement with what has been reported for related alkylating agents. The main reaction products in Hb were 2-hydroxyethylations of cysteine, N-terminal valine, the two imidazole nitrogens in histidine and carboxylic groups. The reactivities of human, mouse and rat Hb towards EtO were compared. The main difference between species was the 12 and 170 times higher reactivity of cysteine in mouse and rat Hb, respectively, than in human Hb. As expected from relative reactivities of alkylating agents with model nucleophiles, products with cysteine dominated for EtO (except in human Hb) whereas for HOEtNU products with carboxylic groups were far larger than any other. Relative amounts of cysteine and carboxylic group alkylation in mouse Hb were compared with corresponding data for other alkylating agents. The comparison showed that these amounts were close to what could be expected from known reactivities of these compounds with model nucleophiles, but that sterical and other modifying factors have to be taken into account. Each compound gives therefore a species-specific pattern that might be used for tracing human exposure of unknown origin.
Carcinogenesis 1990 Feb
PMID:Reaction products in hemoglobin and DNA after in vitro treatment with ethylene oxide and N-(2-hydroxyethyl)-N-nitrosourea. 230 58

Hepatic S-[2-(N7-guanyl)ethyl]glutathione DNA adducts were determined in several strains of rats and mice after i.p. injection of a dose of 37 mg ethylene dibromide/kg body wt. More adducts were formed in rats than in mice, while no difference was noted among strains within each species. Removal of adducts in liver DNA was relatively slow in all animals tested. On the contrary, in vitro incubation of calf thymus DNA with ethylene dibromide and either rat cytosol or mouse cytosol gave rise to similar amounts of adduct, yet mouse cytosol showed much higher glutathione (GSH) S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Human cytosol also activated ethylene dibromide, with the extent of conjugation being approximately half that of rat cytosol. Pretreatment of rats with phenobarbital or beta-naphthoflavone induced GSH S-transferases but did not increase the in vivo formation of DNA adducts, suggesting that concomitant induction of cytochrome P450 might abolish the effect of induction of GSH S-transferase by increasing the oxidation of ethylene dibromide. Butylated hydroxytoluene induced GSH S-transferase and also markedly increased DNA adduct levels. Disulfiram, a known cytochrome P450 inhibitor, significantly increased the formation of DNA adducts whereas it did not affect GSH S-transferase activity. Depletion of GSH by pretreatment of rats with diethylmaleate or buthionine sulfoximine resulted in decreased in vivo DNA adduct levels and the degree of reduction was well correlated with the extent of GSH depletion. In vitro incubation of tritiated S-(2-hydroxyethyl)GSH with calf thymus DNA in the presence of 3'-phosphoadenosine-5'-phosphosulfate and rat liver cytosol did not result in significant binding to DNA, suggesting that sulfation of the alcohol does not readily occur to add a leaving group and regenerate an episulfonium ion. These results suggest that induction of the Phase II enzyme GSH S-transferase can be detrimental in the case of ethylene dibromide and that decreases in GSH levels reduce DNA alkylation in rats.
Carcinogenesis 1990 Mar
PMID:Formation of the DNA adduct S-[2-(N7-guanyl)ethyl]glutathione from ethylene dibromide: effects of modulation of glutathione and glutathione S-transferase levels and lack of a role for sulfation. 231 Nov 85

Ethylene oxide, diethyl sulphate and dimethyl sulphate were used to synthesize the corresponding 7-alkylation products of 2'-deoxyguanosine 3'-monophosphate (dGMP). The purified adducts were used as substrates in the 32P-post-labelling reaction with T4 polynucleotide kinase. The kinetics of phosphorylation were studied with 7-(2-hydroxyethyl)-dGMP: most net product was formed by 15 min and only a small increase was seen until 4 h. When different concentrations of the adducts were tested, a complete phosphorylation was noted for 7-methyl-dGMP to the lowest tested amount of 1 fmol. The efficiencies of phosphorylation for 7-ethyl- and 7-hydroxyethyl-dGMP were 1.5 and 0.5% respectively. The proportions phosphorylated were uniform over the concentration range tested. The results demonstrate dramatic differences in the efficiency of phosphorylation between structural analogues, which is probably related to a decreased affinity of the substrate to the enzyme or to an interference in the transfer of the phosphate group on the active site of the enzyme.
Carcinogenesis 1990 Aug
PMID:32P-postlabelling of 2-hydroxyethylated, ethylated and methylated adducts of 2'-deoxyguanosine 3'-monophosphate. 238 26

Toxicology and carcinogenesis studies of 2 structurally-related p-phenylenediamines, HC Blue No. 1, and HC Blue No. 2 were conducted by administering each chemical in feed for 103 weeks to both sexes of Fischer 344/N rats and B6C3F1 (C57BL/6N x C3H/HEN) mice. Diets containing 0, 1500, or 3000 ppm HC Blue 1 were fed to male and female rats and male mice; female mice received diets with 0, 3000, or 6000 ppm. Diets containing 0, 5000, or 10,000 ppm HC Blue 2 were fed to male rats and mice and the females received diets containing 0, 10,000 or 20,000 ppm. These concentrations were compatible with long-term growth and survival. The results demonstrated substantial differences in the neoplastic and non-neoplastic lesions caused by these structural analogs. HC Blue 2 caused histocytosis in lungs and hyperostosis of the skull in rats, and splenic hematopoiesis, fibrous osteodystrophy, and hyperostosis of the skull in mice. These non-neoplastic lesions were not observed in rats or mice treated with HC Blue 1. Contrasting, in male and female mice, HC Blue 1 produced dose-related increases in the incidences of both adenomas and carcinomas of the liver. HC Blue 1 produced a marginally positive trend in hepatocellular nodules and carcinomas in male rats and dose-related increases in hyperplasias and neoplasms of the lungs in female rats. In contrast, there was no evidence of carcinogenicity for HC Blue 2 in either sex of rats or mice, despite the fact that it was administered 3-5 times the dose of the HC Blue 1. Since these 2 nitroaromatic compounds differ only in the methyl vs. 2-hydroxyethyl substituent on the secondary amine of ring carbon 4, the great discordance in their carcinogenicity is most probably due to side group-directed alteration in their metabolic profiles.
 ...
PMID:Comparative carcinogenicity of two structurally similar phenylenediamine dyes (HC blue no. 1 and HC blue no. 2) in F344/N rats and B6C3F1 mice. 273


1 2 3 4 5 6 Next >>