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

To establish an in vitro system for studying DNA repair, bleomycin-induced unscheduled DNA synthesis in permeable HeLa cells was investigated. Permeable HeLa cells were incubated at 0 degree C for 60 min with 0.11 mM bleomycin, washed to remove free bleomycin and assayed for DNA synthesis. Optimum [3H]deoxythymidine monophosphate incorporation occurred at pH 7.6-8.0 (adjusted at 20 degrees C with Tris-HCl buffer), 3-6 mM MgCl2, 40-60 mM NaCl, and 2.5-5 mM ATP in the presence of four deoxynucleoside triphosphates. The unscheduled nature of DNA synthesis in bleomycin-pretreated permeable cells was confirmed by the BrdUMP density shift technique. Exonuclease III sensitivity of repaired DNA was measured to determine whether or not the completion of repair patches and ligation occurred in bleomycin-pretreated permeable cells. Gap-filling and ligation were suggested to occur in the presence of ATP. Studies using the selective inhibitors (aphidicolin, 2',3'-dideoxythymidine 5'-triphosphate and N-ethylmaleimide) for DNA synthesis showed that DNA polymerases alpha and beta were involved in the repair process. Inhibitor studies suggested that DNA polymerase alpha plays a preferential role in repair label in the intranucleosomal region of nuclear chromatin and DNA polymerase beta in the completion of repair patches in bleomycin-pretreated permeable cells.
Carcinogenesis 1986 Jan
PMID:DNA repair synthesis in bleomycin-pretreated permeable HeLa cells. 241 38

At least 6 N-acetylglucosaminyltransferases (GlcNAc-T I, II, III, IV, V and VI) are involved in initiating the synthesis of the various branches found in complex asparagine-linked oligosaccharides (N-glycans), as indicated below: GlcNAc beta 1-6 GlcNAc-T V GlcNAc beta 1-4 GlcNAc-T VI GlcNAc beta 1-2Man alpha 1-6 GlcNAc-T II GlcNAc beta 1-4Man beta 1-4-R GlcNAc T III GlcNAc beta 1-4Man alpha 1-3 GlcNAc-T IV GlcNAc beta 1-2 GlcNAc-T I where R is GlcNAc beta 1-4(+/- Fuc alpha 1-6)GlcNAcAsn-X. HPLC was used to study the substrate specificities of these GlcNAc-T and the sequential pathways involved in the biosynthesis of highly branched N-glycans in hen oviduct (I. Brockhausen, J.P. Carver and H. Schachter (1988) Biochem. Cell Biol. 66, 1134-1151). The following sequential rules have been established: GlcNAc-T I must act before GlcNAc-T II, III and IV; GlcNAc-T II, IV and V cannot act after GlcNAc-T III, i.e., on bisected substrates; GlcNAc-T VI can act on both bisected and non-bisected substrates; both Glc-NAc-T I and II must act before GlcNAc-T V and VI; GlcNAc-T V cannot act after GlcNAc-T VI. GlcNAc-T V is the only enzyme among the 6 transferases cited above which can be essayed in the absence of Mn2+. In studies on the possible functional role of N-glycan branching, we have measured GlcNAc-T III in pre-neoplastic rat liver nodules (S. Narasimhan, H. Schachter and S. Rajalakshmi (1988) J. Biol. Chem. 263, 1273-1281). The nodules were initiated by administration of a single dose of carcinogen 1,2-dimethyl-hydrazine.2 HCl 18 h after partial hepatectomy and promoted by feeding a diet supplemented with 1% orotic acid for 32-40 weeks. The nodules had significant GlcNAc-T III activity (1.2-2.2 nmol/h/mg), whereas the surrounding liver, regenerating liver 24 h after partial hepatectomy and control liver from normal rats had negligible activity (0.02-0.03 nmol/h/mg). These results suggest that GlcNAc-T III is induced at the pre-neoplastic stage in liver carcinogenesis and are consistent with the reported presence of bisecting GlcNAc residues in N-glycans from rat and human hepatoma gamma-glutamyl transpeptidase and their absence in enzyme from normal liver of rats and humans (A. Kobata and K. Yamashita (1984) Pure Appl. Chem. 56, 821-832).
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PMID:The biosynthesis of highly branched N-glycans: studies on the sequential pathway and functional role of N-acetylglucosaminyltransferases I, II, III, IV, V and VI. 297 90

Semi-permeable magnetic polyethyleneimine (PEI) microcapsules have been developed to trap carcinogens and their metabolites in vivo and their time-dependent binding of a model carcinogen, [14C]benzo[a]pyrene [( 14C]BaP), is studied within the intestinal lumen. Overall, approximately 0.5% of an intragastric BaP dose was bound by these microcapsules recovered from faeces with specific binding of metabolites (nmol/10(6) recovered microcapsules) being similar in the 0-24-h and 24-48-h periods, but approximately 10-fold lower in the 48-72-h period. Successive extractions of microcapsules with ammoniacal methanol, 2.5 N HCl, methanol and dimethylsulfoxide released approximately 60% of bound radiolabeled and the unextracted radiolabel was presumed to have been bound covalently. By contrast, greater than 90% of bound radiolabel was extractable from the faeces of the treated animals and from microcapsules treated in vitro with [14C]7,8-dihydroxy-9,10-epoxytetrahydrobenzo[a]pyrene (BaPDE), indicating that the in vivo microcapsule-bound metabolites were not derived either from adsorbed faecal material or from [14C]BaPDE formed in situ. A time-dependent appearance of BaP 3,6-dione was found. Also the qualitative and quantitative patterns of metabolites trapped by microcapsules, as assayed by h.p.l.c., were consistent only with a unique set of BaP metabolites being bound within the intestinal lumen. Hence these carcinogen-binding microcapsules can be used to investigate the in situ formation of carcinogen metabolites within the intestinal tract.
Carcinogenesis 1987 Jun
PMID:Binding of benzo[a]pyrene metabolites in the rat intestinal lumen by magnetic polyethyleneimine microcapsules following an intragastric dose of [14C]benzo[a]pyrene. 360 80

Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 wk. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1 N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the 300-ppm dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower than that in controls. Mean body weight was reduced in 300-ppm-dose female rats and 300-ppm-dose male and female mice compared to controls. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Under the conditions of these studies, there was clear evidence of carcinogenicity for F344/N rats and for B6C3F1 mice in that 4,4'-methylenedianiline dihydrochloride caused increased incidences of (1) follicular-cell carcinomas of the thyroid gland (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%; p less than or equal to 0.012) and neoplastic nodules of the liver (controls, 1/50, 2%; low dose, 12/50, 24%; high dose, 25/50, 50%; p less than or equal to 0.001) in male rats, (2) follicular-cell adenomas (controls, 0/47; low dose, 2/47, 4%; high dose, 17/48, 35%; p less than or equal to 0.001) and C-cell adenomas (controls, 0/47; low dose, 3/47, 6%; high dose, 6/48, 13% p less than or equal to 0.029) of the thyroid gland in female rats, (3) follicular-cell adenomas of the thyroid gland (controls, 0/47; low dose, 3/49, 6%; high dose, 16/49, 33%; p less than or equal to 0.001), carcinomas of the liver (controls, 10/49, 20%; low dose, 33/50, 66%; high dose, 29/50, 58%; p less than or equal to 0.001), and pheochromocytomas of the adrenal gland in male mice (controls, 2/48, 4%; low dose, 12/49, 24%; high dose, 14/49, 29%; p less than or equal to 0.001), and (4) follicular-cell adenomas of the thyroid gland (controls, 0/50; low dose, 1/47, 2%; high dose, 13/50, 26%; p less than or equal to 0.001), carcinomas (controls, 1/50, 2%; low dose, 6/50, 12%; high dose, 11/50, 22%; p less than or equal to 0.002) and adenomas (controls, 3/50, 6%; low dose, 9/50, 18%; high dose, 12/50, 24%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1 mice. 371 94

At low doses, N-nitrosomethylethylamine (NMEA) selectively produces liver tumors in rats, whereas beta-trideuterated NMEA also includes esophageal carcinomas under these conditions. Since deuteration is capable of retarding enzymic hydroxylation, these studies suggest that beta-hydroxylation plays a significant role in the organ specificity of NMEA. To test the hypothesis that this metabolic pathway occurs in vivo to yield a hydroxyethylating intermediate, we have determined the extent of hydroxyethylation of hepatic DNA in male Fischer 344 rats following a single i.p. injection of [1-ethyl-14C]NMEA (6.3 mg/kg, 4 h survival). After hydrolysis in 0.1 M HCl, DNA purines were analysed by cation exchange chromatography. Of the major alkylpurines identified, 7-ethylguanine (7-etG) (6.7 mumol/mol guanine) and O6-ethylguanine (4.1 mumol/mol guanine) comprised 13 and 8% of the eluted radioactivity, respectively. 7-(2-Hydroxyethyl)guanine (7-heG) was the only hydroxyethyl adduct detectable, and comprised less than 2% of the amount of 7-etG. 3-Ethylguanine and 3- and 7-ethyladenine were also identified as products of NMEA metabolism. Similar analyses were carried out on hepatic DNA from rats treated with N-nitrosodi[1-14C]ethylamine (6.9 mg/kg, 4 h survival). Only trace amounts of 7-heG could be detected. The very low concentrations of beta-hydroxyethylated DNA bases observed suggest that this route of metabolism does not contribute significantly to the carcinogenicity of these compounds.
Carcinogenesis 1986 Aug
PMID:Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo. 373 87

Synchronous scanning fluorescence with a fixed wavelength difference (delta lambda) of 34 nm between excitation and emission was used to quantitate benzo[a]pyrene-diol epoxide (BPDE)-DNA adducts. Fluorescence emission maxima occurred at 382 nm for BPDE-DNA and at 379 nm for benzo[a]pyrene-tetrols and -triol, which are hydrolysis products of BPDE. Similarly, the peak for pyrene was at 372 nm and for 1-nitropyrene at 386 nm. The minimum detectable amount of BPDE-moieties in in vitro modified BPDE-DNA, after hydrolysis in HCl, was 20 fmol in 100 micrograms of DNA, which is equivalent to 1 adduct per 1.4 X 10(7) nucleotides. The correlation of fluorescence intensity and the amount of BPDE-moieties was linear between 20 fmol and 1 pmol. DNA isolated from human lymphoblasts incubated with BPDE had the same fluorescence peak and the correlation between the fluorescence intensity and the amount of BPDE in the incubation mixture was linear. Among the DNA-samples from peripheral blood lymphocytes of 30 aluminum plant workers, only one sample was found to contain a peak similar to BPDE-DNA. None of the DNA-samples from 10 persons not occupationally exposed were positive. Measurement of BPDE-DNA adducts by synchronous fluorescence spectrophotometry should be useful in monitoring human exposure to benzo[a]pyrene.
Carcinogenesis 1985 Aug
PMID:An applied synchronous fluorescence spectrophotometric assay to study benzo[a]pyrene-diolepoxide-DNA adducts. 392 34

In primary monolayer cultures of mature rat hepatocytes, cell growth and hepatocyte-specific functions were mediated by a cell surface component (named the cell surface modulator) via cell-cell contact. The modulator activity was heat-labile and trypsin-sensitive. Activity was also found in plasma membranes from kidney, brain, lung, and erythrocytes. The modulator was solubilized by 4% octylglucoside plus 4M guanidine HCl from liver membranes. The molecular weight of the modulator was 670KD determined by Sephacryl S-400 gel filtration. Hepatoma cells established from Reuber and Morris hepatoma did not show any cell density-dependency on either cell growth or hepatocyte-specific function. However, these hepatoma cells had strong cell surface modulator activity. These results suggest that hepatoma cells have lost their cell density-dependent regulation because they have lost the ability to respond to the cell surface modulator. Characterization of the cell surface modulator and its mechanism of transmitting a signal for gene regulation would be helpful in understanding the process by which cells assemble into tissues in vivo and the mechanism of changes in gene expression in tissue during development, regeneration and carcinogenesis.
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PMID:[Reciprocal regulation of growth and differentiation in hepatocytes by cell surface modulator and loss of regulation during carcinogenesis]. 398 39

A simple and sensitive method was developed for quantification of mutagenic/carcinogenic aminoimidazoquinoline and aminoimidazoquinoxaline compounds in heated materials. Samples were partially purified by blue-cotton treatment, 0.1 N HCl-methylene dichloride partition and separation in a SEP-PAK silica cartridge. The recoveries of aminoimidazoquinoline and aminoimidazoquinoxaline compounds at the step of partial purification were estimated by spiking with 14C-labeled compounds. The compounds in partially purified materials were analyzed by liquid chromatography with electrochemical detection using a combination of two columns of octadecyl silane and cation exchange. Bacteriological-grade beef extract was found to contain 41.6 and 58.7 ng/g of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), respectively. MeIQx was also detected at a level of 3.1 ng per g in food-grade beef extract.
Carcinogenesis 1985 Aug
PMID:Quantification of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in beef extracts by liquid chromatography with electrochemical detection (LCEC). 401 87

The hypolipidaemic drug nafenopin (NAF) has been shown to enhance the hepatocarcinogenic effect of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine in rats. We have investigated whether the NAF-induced peroxisome proliferation in hepatocytes interferes with NDMA's metabolism and interaction with DNA. Adult male Wistar rats received a single i.p. injection of [14C]NDMA (2 mg/kg) and were killed 4 h later. DNA was isolated from liver and kidney, hydrolysed in 0.1 N HCl and analysed by Sephasorb chromatography. In rats pre-treated with NAF (0.2% in the diet over a period of 3 weeks), the concentration of N7-methylguanine in hepatic DNA (mumol/mol guanine) was 46% below control values. This is probably due to the greater amount of target DNA, as NAF caused a marked hepatomegaly with a 50% increase in total liver DNA content. Concentrations of N7-methylguanine in kidney DNA were twice as high in NAF-pre-treated animals when compared to control rats. This is unlikely to result from a shift in the metabolism of NDMA from liver to other rat tissues since the time course and extent of the conversion of [14C]NDMA to 14CO2 and 14C-labelled urinary metabolites were identical in NAF-treated and control animals. There was no indication that NAF inhibits the activity of the hepatic O6-alkylguanine-DNA alkyltransferase.
Carcinogenesis 1985 Sep
PMID:Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo. 402 30

The possible intragastric nitrosation of ranitidine to genotoxic derivatives has been investigated in rats and mice given, by gavage, high single doses of this histamine H2 receptor antagonist along with NaNO2. Liver DNA fragmentation, as revealed in rats by both DNA alkaline elution and DNA alkaline denaturation followed by hydroxylapatite chromatography, was found to be dependent either on the molar ratio drug/nitrite or on the gastric pH. It occurred only with doses of 175 mg/kg ranitidine HCl + 80 mg/kg NaNO2 (molar ratio 1:2.32) or 350 mg/kg ranitidine HCl + 80 mg/kg NaNO2 (molar ratio 1:1.16) and concurrent reduction of gastric pH from 5.5 to 2-3 (produced by prolonged fasting). A further reduction of pH elicited by histamine injection increased the amount of DNA damage. DNA fragmentation in gastric mucosa showed a similar dependence on both pH and ranitidine/NaNO2 ratio, but was more marked than in liver. Simultaneous administration of ascorbic acid reduced the damage of gastric DNA. Oral administration of 175 mg/kg ranitidine HCl + 80 mg/kg NaNO2 in fasted and histamine-injected mice induced a modest but statistically significant increase in the frequency of sister chromatid exchanges in bone marrow cells.
Carcinogenesis 1983 Oct
PMID:Genotoxic effects in rodents given high oral doses of ranitidine and sodium nitrite. 631 51


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