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)

Soluble nickel(II) ion, given to male F344/NCr rats as a single i.p. injection of nickel(II) acetate tetrahydrate at a dose of 90 mumols/kg body weight at 5 weeks of age, proved an effective initiator of renal cortical epithelial tumors. The tumors were revealed by subsequent dosing with the known renal tumor promoter, sodium barbital (5,5-diethylbarbituric acid, sodium salt) dissolved in drinking water at a concentration of 500 p.p.m. Only one rat given the nickel injection without subsequent promotion developed a single renal cortical adenoma, while multiple tumors were common in nickel(II) initiated/sodium barbital promoted rats. Renal cortical adenocarcinomas, some of them metastatic to lung, liver, and spleen, occurred only in initiated/promoted rats. No excess incidence of nickel-initiated tumors was found in any other tissues in which sodium barbital is known to promote carcinogenesis, such as liver or thyroid. A single i.p. injection of the Ni(II) salt, 95 mumols/kg, appeared to be associated with an increased concentration of 8-hydroxy-2'-deoxyguanosine in DNA extracted from kidneys of rats 16-48 h after injection.
Carcinogenesis 1990 Apr
PMID:Initiation by nickel acetate and promotion by sodium barbital of renal cortical epithelial tumors in male F344 rats. 232 3

Continuous dietary administration of the hepatocarcinogen 2-acetylaminofluorene (AAF) to rats produces a gradual increase in hepatic DNA adducts until a plateau is reached after approximately 2 weeks. The rate of DNA adduct formation remains constant through 1 month of AAF feeding, while adduct removal profiles are biphasic during both carcinogen feeding and subsequent time on control diet. In the present experiments, we tested the hypothesis that biphasic adduct removal is due to differential repair kinetics taking place in different chromatin fractions. Rats were fed 0.02% AAF for times up to 30 days and control diet for a subsequent 28 days. HPLC analysis of nuclear DNA indicated that the deacetylated adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, comprised approximately 90% of the total C8-substituted deoxyguanosine adducts after 3 days of feeding and greater than 98% after 20 days. The nuclear DNA was partitioned into endogenous nuclease sensitive (approximately 2%), low salt soluble (approximately 70%), high salt soluble (approximately 20%) and nuclear matrix (approximately 8%) fractions. During 28 days of AAF feeding, each fraction showed a profile of adduct formation similar to that observed in whole nuclei; however, the adduct concentration in nuclear matrix-associated DNA was consistently less than that in the other fractions. In rats fed AAF for 28 days followed by control diet, adduct removal in each of the fractions showed biphasic kinetics that were similar to those observed in nuclear DNA. When rats were fed AAF for 7 days, however, adduct removal kinetics could be best described by a single first-order rate constant. These data indicate that biphasic adduct removal may be due to the presence of particular nucleotide sequences that are common to all fractions and are relatively resistant to adduct formation and removal. The low concentration of adducts found in the nuclear matrix may be due to a decreased rate of adduct formation in this region and/or the proximity of membrane-bound beta-polymerases that are responsible for repair.
Carcinogenesis 1990 Aug
PMID:DNA adduct formation and removal in hepatic chromatin fractions from rats chronically fed 2-acetylaminofluorene. 238 20

For the past 60 years, fundamental discoveries in eukaryotic biology using mammalian cell cultures have been significant but modest relative to the enormous potential. Combined with advances in technologies of cell and molecular biology, mammalian cell culture technology is becoming a major, if not essential tool, for fundamental discovery in eukaryotic biology. Reconstruction of the milieu for cells has progressed from simple salt solutions supporting brief survival of tissues outside the body to synthesis of the complete set of structurally defined nutrients, hormones and elements of the extracellular matrix needed to reconstruct complex tissues from cells. The isolation of specific cell types in completely defined environments reveals the true complexity of the mammalian cell and its environment as a dynamic interactive physiological unit. Cell cultures provide the tool for detection and dissection of the mechanism of action of cellular regulators and the genes that determine individual aspects of cell behavior. The technology underpins advances in virology, somatic cell genetics, endocrinology, carcinogenesis, toxicology, pharmacology, hematopoiesis and immunology, and is becoming a major tool in developmental biology, complex tissue physiology and production of unique mammalian cell-derived biologicals in industry.
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PMID:Frontiers in mammalian cell culture. 240 11

Alterations in DNA-protein interactions (DPI) may play an important role in carcinogenesis. Although the mechanism of nickel carcinogenesis is unknown, nickel reportedly affects DPI. A microfiltration, nitrocellulose filter assay was utilized to study DPI in intact Chinese hamster ovary (CHO) cells and in isolated nuclei. Prior to exposure of CHO cells or isolated CHO cell nuclei, DNA and proteins were radiolabeled using 3H-thymidine and 35S-methionine, respectively. Nuclei were exposed to NiCl2 in 10 mM HEPES buffer (pH 6.8). CHO cells were exposed in either complete or a salts-glucose medium. Following exposure, nuclei or cells were incubated at 37 degrees C for 20 min in a high salt lysis solution; aliquots were loaded onto nitrocellulose filters and washed with a low salt solution. DNA (3H) retained on each filter was normalized to protein (35S) bound on the filter. Exposure of either whole cells or isolated nuclei to increasing, noncytotoxic concentrations of NiCl2 resulted in a dose dependent decrease in DPI. The effect of nickel on specific DNA-protein interactions was examined using a band shift assay and a cloned satellite DNA sequence. Nickel inhibited specific protein binding to the satellite DNA probe. The results of these two independent assays, which were conducted at physiological pH, indicate that NiCl2 inhibits specific DNA-protein interactions.
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PMID:Effect of nickel(II) on DNA-protein interactions. 248 78

According to certain hypotheses, the production of oxygen radicals within the biological medium (the phenomenon of oxidative stress) may play an important role in fibrosis and in certain steps of carcinogenesis. The mineral fibres of various materials are capable of participating in this phenomenon, owing to the reducing nature of their surface activity, so that OH. radicals can be produced from oxygen in 3 steps. The surface activity of inorganic materials which are insoluble or only very slightly soluble is due to the presence of electron donor active sites, generally linked to Fe2+ ions found in the neighbourhood of the surface. In biological systems, these sites may emerge on the surface as a result of the partial dissolution of the particle, the action of a biological reducing agent, the phenomenon of deposition on the surfaces or cation exchange. We have explored the reducing properties of the surfaces of a certain number of mineral fibres, in aqueous buffer medium, by electron paramagnetic resonance (EPR) measurement of the adduct with the radical-trapping agent 5,5'-dimethyl-l-pyrrolidine-N-oxide (DMPO), produced from the radicals initially formed (OH. or R.). We have found certain fibres to be highly effective in producing radicals from dissolved oxygen (Canadian chrysotile, nemalite, freshly ground amphiboles) while others have little effect. The reducing activity of certain fibres may be markedly increased by prior treatment in the presence of a ferrous salt (as in the case of erionite) or by the addition of glutathione to the reaction medium (as in the case of UICC crocidolite). It is suggested that the carcinogenic activity of certain inorganic materials at the pulmonary level is the result of their surface reducing properties. These reducing properties may either be present at the time of inhalation or acquired in the biological medium. This hypothesis is not in conflict with the observation of the role of the dimensional characteristics of fibres in mesothelioma.
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PMID:Production of oxygen radicals by the reduction of oxygen arising from the surface activity of mineral fibres. 254 1

We previously reported a rapid production model for pancreatic carcinoma development in Syrian hamsters incorporating the principle of selection by resistance to cytotoxicity. In the present experiment, the efficacy of repeated augmentation pressure with regard to generation of pancreatic lesions in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) was investigated. Forty-eight female Syrian golden hamsters were divided into four groups according to the frequency of augmentation pressure. Group 1 received 70 mg/kg body weight of BOP and three injections of 20 mg/kg BOP. Groups 2-4 received 70 mg/kg BOP followed by one, two or three cycles of augmentation pressure consisting of dl-ethionine on sugar and salt diet, l-methionine and 20 mg/kg BOP. Hamsters were killed 10 weeks after the beginning of the experiment and the resultant incidences of pancreatic carcinomas from groups 1-4 were 0, 30, 50 and 46.2% respectively, the numbers of pancreatic carcinomas increasing with the frequency of augmentation pressure. A 46.2% yield of cholangiocarcinomas was also observed in group 4. The model should be useful for investigation of potential modulating factors since large numbers of lesions can be induced within a total experimental period of only 10 weeks.
Carcinogenesis 1989 Aug
PMID:Cycles of repeated augmentation pressure in rapid production of pancreatic and cholangiocellular carcinomas in hamsters initiated with N-nitrosobis(2-oxopropyl)amine. 254 90

In a study to determine the effect of saturation of fats on their ability to stimulate cholecystokinin (CCK) release six normal volunteers ate five test meals containing different fats with intervals of 1 week. Plasma CCK levels were measured by a specific radioimmunoassay and the gallbladder volume was calculated from ultrasound measurements. The sodium salt of the monounsaturated fatty acid oleic acid (3.5 g) produced a significantly greater integrated CCK response than that of the saturated fatty acid stearic acid (mean [SEM] 103 [41] vs 8[41] pmol.l-1.min). The gallbladder contracted to 42 (3)% of its initial volume after oleate but remained at 89 (8)% of its initial volume after stearate. Integrated CCK responses to dietary triglycerides (30 g) also differed significantly according to the degree of saturation--277 (58) pmol.l-1.min after corn oil (predominantly diunsaturated), 143 (14) pmol.l-1.min after olive oil (predominantly monounsaturated), and 44 (12) pmol.l-1.min after suet (predominantly saturated). The finding that unsaturated fats are stronger stimulants of CCK release than saturated fats may explain the promotion of pancreatic carcinogenesis in rats by unsaturated but not saturated fats and may support the role of CCK in this effect.
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PMID:Saturation of fat and cholecystokinin release: implications for pancreatic carcinogenesis. 257 43

Changes in urinary parameters (particularly electrolyte levels and pH), and DNA synthesis and the morphology of the bladder epithelium were investigated in rats that were fed for 4 or 8 wk on diets containing various Na, K, Mg or Ca carbonate salts, with or without L-ascorbic acid (AsA). [The carbonate salts were fed at a level of 3% in the diet, and AsA or AsA-Na was administered at 5% in the diet. NH4Cl was at 1% in the diet.] The effects of treatment with NH4Cl (used as a urine acidifier), and of combined treatment with sodium ascorbate (AsA-Na) and NH4Cl were also investigated. Urinary pH was significantly elevated in groups given NaHCO3, K2CO3, AsA + NaHCO3, AsA + K2CO3 and AsA-Na, whereas treatment with AsA or NH4Cl alone caused a significant drop in urinary pH. An increase in urinary electrolytes or ascorbic acid was associated with the corresponding dosing regimen. DNA synthesis in the bladder epithelium was increased in groups given NaHCO3, K2CO3, AsA + NaHCO3, AsA + K2CO3 or AsA-Na. Furthermore, all treatments that induced an elevation of DNA synthesis also induced some morphological alterations in the bladder epithelium. The administration of AsA in conjunction with NaHCO3 or K2CO3 induced levels of change greater than those with either salt alone. In contrast, the degree of response in the bladder epithelium of rats given AsA-Na was reduced by the simultaneous administration of NH4Cl. These results suggest that the degree of DNA synthesis and/or morphological alteration in the rat-bladder epithelium after treatment with various bases may depend on changes in urinary concentrations of Na+ or K+ ions and/or pH, and the presence of ascorbic acid in the urine. The results are discussed in relation to the possible promotion by various treatment regimens (salts +/- AsA) of urinary bladder carcinogenesis.
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PMID:Participation of urinary Na+, K+, pH, and L-ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats. 279 70

In this paper, it is evidenced by the quantitative structure-carcinogenic activity relationship (QSCAR) and the pattern recognition treatment of N-nitroso compounds (NNC) that the key step of carcinogenesis induced by NNC is the cross-linking on the complementary base pair of DNA, through the bifunctional alkylation between alpha-carbon and another carbon within the same chain. The alkylation by the alpha-carbon atom is through the diazonium salt, but that by the atom other than the alpha-position is through the active ester formed from the hydroxylated metabolite of the chain. Therefore, the alkylation by the beta-position of NNC, or by its gamma-position, under suitable conditions, of which the distances from the alpha-position both approach 2.80-3.00 A, would be the most favourable positions along with the alpha-position for the cross-linking to occur between the complementary base pairs of DNA, which will yield the carcinogenic activity of NNC. The above conception of bifunctional alkylation can reduce the QSCAR of NNC to a reasonable structure-chemical reactivity relationship under the complex biological conditions, and is the successful extension of the Di-region theory to the carcinogenesis mechanism of the important NNC series. In the light of the above viewpoint, for 153 NNCs including the nitrosamines and nitrosamides which have been tested reliably with animals, the correct discrimination ratio by quantitative pattern recognition according to carcinogenic activity indexes divided into 5 degrees comes up to as high as 97%.
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PMID:Quantitative pattern recognition for structure-carcinogenic activity relationship of N-nitroso compounds based upon Di-region theory. 281 16

This paper describes in vitro studies on the effects of environmental pollutants (SO2/NOx) in biological systems. Basic physical, chemical and biochemical parameters were analyzed to establish the rate of SO2/NOx absorption by the culture medium. It was shown that the pH remains constant for 24 h of exposure to gas concentrations up to 50 p.p.m. The concentration of ions resulting from absorption of each pollutant in the liquid phase is dependent on their concentration in the gas phase and on exposure time. Short exposure times and high gas dosages resulted in similar doses in the medium as long exposure periods and low gas dosages. The activities of a human serum standard (alkaline phosphatase, ALP; aspartate amino transferase, AST; alanine amino transferase, ALT; gamma-glutamyltransferase, gamma-GT; lactate dehydrogenase, LDH) were determined after gaseous exposure to SO2 and NOx. The results revealed a distinct decrease in the activity of LDH after 1, 3 and 5 h exposure to 200 p.p.m. SO2. The effects of the pollutants were assayed in vitro using fetal hamster lung cells (FHLC), rat hepatocytes and the cell line CO60. For the determination of toxic effects, it was shown that the plating efficiency was a more sensitive parameter than the assay for trypan blue exclusion. Toxicity indicated as an increase of LDH leakage was not observed from FHLC in culture. Instead, a decrease of LDH was found following SO2 exposition. This decrease was similar to that observed for the human serum standard. The induction of DNA single-strand breaks was determined as a measure of genotoxic effects. SO2 application decreased the rate of DNA single-strand breaks induced by N-nitroso-acetoxymethyl-methylamine in both FHLC and in rat hepatocytes. SO2 or NOx treatment of CO60 cells for 1 h did not result in the induction of DNA amplification. HSO3- added directly to the medium as the sodium salt, however, distinctly induced the amplification of SV40 DNA. The amplification rates induced by benzo[a]pyrene or dimethylbenzanthracene were neither influenced by SO2, NOx nor HSO3-. An additive effect of HSO3- with either benzo[a]pyrene or dimethylbenzanthracene for this biological parameter was therefore not observed.
Carcinogenesis 1988 Jul
PMID:Effects of SO2 or NOx on toxic and genotoxic properties of chemical carcinogens. I. In vitro studies. 283 97


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