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

Inductions of oxidative DNA damage (oh8dG) in vitro and peritoneal mesothelioma in rats (F344, female) were compared between crocidolite (CR) and de-ironized crocidolite [DCR, washed by HCl and ethylenediamine tetraacetic acid (EDTA)] to verify the hypothesis that reactive oxygen species contribute to carcinogenesis, focusing on the role of iron present inside or outside of the CR. The yield of oh8dG was 14.6 oh8dG/10(5)dG in CR and 30.2 in DCR under simple incubation with DNA. In the incubation systems added several chemicals and H2O2, DCR induced higher levels of oh8dG than CR. Especially, the addition of Fe2O3 and H2O2 to DCR increased oh8dG in DNA depending on the Fe2O3 concentration, however, this tendency was not observed in the same system of CR. Surprisingly, 7 out of 10 rats died within 2 days after the injection of 10 mg of Fe2O3 following the DCR injection (5 mg/rat), showing necroses of hepatocytes from the surface of each lobe where CR and Fe2O3 particles had been deposited together. There was no death in other groups of rats. One year after the i.p. injection of CR (5 mg/rat, single injection), mesotheliomas were found in all rats administered DCR and Fe2O3 (2 mg/rat, once a week, for 35 weeks), in 4 rats of DCR alone (n = 10), in 5 rats of CR alone (n = 10) and in none of the rats administered Fe2O3 alone (n = 10). Therefore, present results indicate that the induction of oxidative DNA damage changed even when the same type of asbestos was washed by chemical treatment, and Fe2O3 promoted the development of mesothelioma which was induced by DCR.
Carcinogenesis 1994 Apr
PMID:Inductions of oxidative DNA damage and mesothelioma by crocidolite, with special reference to the presence of iron inside and outside of asbestos fiber. 814 91

The capability of Cr(III) to induce DNA lesions generated by oxidative damage was investigated in this study by examining the formation of 8-hydroxydeoxyguanosine (8-OHdG) in calf thymus DNA by CrCl3 and/or H2O2 in 10 mM phosphate buffer. In the presence of 0.5 mM H2O2, the formation of 8-OHdG markedly increased with increasing CrCl3 concentration. In contrast, H2O2 or CrCl3 alone did not cause any increase in 8-OHdG level above background. The amount of 8-OHdG induced by CrCl3 plus H2O2 was time dependent; its generation increased linearly over an incubation period of 90 min. The formation of 8-OHdG was unfavorable in an acidic solution (pH < 6); the highest level of 8-OHdG was observed at pH 7-8. Scavengers of reactive oxygen species markedly inhibited the formation of 8-OHdG by CrCl3 plus H2O2; the inhibition effect was sodium azide > D-mannitol > Tris-HCl at an equal concentration. The induction of 8-OHdG by CrCl3 plus H2O2 remained unchanged in D2O. Moreover, an addition of catalase (2.2 U/ml) to the reaction mixture completely inhibited the formation of 8-OHdG by CrCl3/H2O2, whereas only 22% of that formation was inhibited by superoxide dismutase (11 U/ml). A large amount of bovine serum albumin (1.1 mg/ml) could reduce the formation of 8-OHdG by CrCl3 plus H2O2, thereby implying that Cr(III)-mediated DNA-protein crosslinks are unfavorable for 8-OHdG formation. Furthermore, ascorbate could prevent the formation of 8-OHdG by CrCl3 plus H2O2; the extent of prevention increased with increasing ascorbate concentration (10 microM-3 mM). Thus, ascorbate acts as a free radical scavenger in the CrCl3/H2O2 system. The above findings suggest that Cr(III)/H2O2 could generate oxidative damage to DNA, possibly through a Fenton-like reaction, i.e. Cr(III)+H2O2-->Cr(IV)+.OH+OH-. This study also indicates that Cr(III), previously considered as the ultimate kinetically stable species of Cr(VI) metabolites, is capable of inducing carcinogenic lesions through interaction with a cellular oxygen species.
Carcinogenesis 1996 Jan
PMID:Induction of 8-hydroxydeoxyguanosine in DNA by chromium(III) plus hydrogen peroxide and its prevention by scavengers. 856 17

Consumption of fossil fuels has increased indoor and outdoor concentrations of polycyclic aromatic hydrocarbons (PAHs) and nitrogen dioxide (NO2). To study the combined effect of PAH administration and NO2 exposure on mutagenicity of urine from animals we injected 400 mg/kg body wt i.p. one of five kinds of PAH (pyrene, fluoranthene, fluorene, anthracene and chrysene) into ICR mice, Wistar rats, Syrian golden hamsters or Hartley guinea pigs after exposure to 20 p.p.m. NO2 gas for 24 h and then exposed the animals to NO2 gas for an additional 24 h. During the latter 24 h we collected the urine and assayed its mutagenicity with the Ames Salmonella strains after treatment with beta-glucuronidase and arylsulfatase and extraction with dichloromethane. The urine from mice treated with both PAH and NO2 showed high mutagenicity for Salmonella typhimurium strains TA98 and TA100, whereas the urine from mice treated with PAH and air showed almost no mutagenic activity. The mutagenicity was decreased in nitroreductase- and acetyltransferase-deficient strains TA98NR and TA98/1,8-DNP6 respectively. Treatment with a mixture of 20% of each of the five kinds of PAH and NO2 augmented the urinary mutagenicity of mice 1.5-fold. The urine from hamsters treated with pyrene or fluoranthene and NO2 was also highly mutagenic, but that from rats or guinea pigs was not very mutagenic. The mutagenicity was also decreased in strains TA98NR and TA98/1,8-DNP6. These results suggest that the urine contains nitro compounds and that the nitration of PAHs occurs in the body of animals under exposure to NO2 gas. Actually, the nitrated metabolites of pyrene, 1-nitro-6/8-hydroxypyrene and 1-nitro-3-hydroxypyrene, were detected in the urine from mice treated with pyrene under exposure to NO2 gas. To elucidate the mechanism of in vivo nitration, NO2 (20 p.p.m.) was bubbled through 50 mM Tris-HCl buffer (pH 7.4) or dichloromethane solution containing pyrene or 1-hydroxypyrene (10 microg/ml). Pyrene was not nitrated by NO2 in either aqueous or organic solutions. However, 1-hydroxypyrene was changed to nitrohydroxypyrenes by NO2 in the Tris-HCl buffer, but not in the organic solution. Ascorbic acid, alpha-tocopherol, glutathione oleic acid and hemoglobin were found to inhibit the nitration of 1-hydroxypyrene in aqueous solution. The urinary mutagenicity of mice treated with both pyrene and NO2 was also decreased by oral administration of ascorbic acid and alpha-tocopherol. These results suggest that 1-hydroxypyrene is nitrated by an ionic reaction in the animal body after hydroxylation of pyrene in the liver.
Carcinogenesis 1996 Jul
PMID:In vivo formation of mutagens by intraperitoneal administration of polycyclic aromatic hydrocarbons in animals during exposure to nitrogen dioxide. 870 53

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces aberrant crypt foci (ACFs) as well as colon cancer in F344 male rats. Conditions allowing rapid development of ACFs over a short period were investigated. F344 male rats were fed 400 ppm of PhIP x HCl in a low-fat diet (LF) for 2 weeks and then given a PhIP-free, high-fat diet containing PRIMEX (HF-PR) or safflower oil, or PhIP-free LF for 4 or 12 weeks. Rats fed HF-PR for 4 weeks gave the highest number of ACFs/rat (3.3) and their size in terms of aberrant crypts/ACF (2.7) was much larger than that obtained with conventional continuous feeding of PhIP for 25 weeks in the CE-2 diet. Therefore, 2 weeks of dietary exposure to 400 ppm of PhIP x HCl, followed by HF-PR for 4 weeks, is a practical and convenient method for obtaining ACFs. This protocol should be useful for studies of the early phase of colon carcinogenesis.
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PMID:Efficient method for rapid induction of aberrant crypt foci in rats with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 895 59

Recent reports indicate that both orally administered and topically applied alpha-tocopherol (vitamin E, TH) prevent UVB-induced skin carcinogenesis in mice. Because UVB exposure causes the formation of oxidants associated with tumor promotion, epidermal TH status may be an important determinant of susceptibility to photocarcinogenesis. To test this hypothesis, we studied the status of epidermal TH in C3H mice following exposure to single and repeated UVB exposures at doses typical of chronic photocarcinogenesis protocols. Exposure of mice to a single 13 kJ/m(2) dose over 60 min resulted in no acute depletion of epidermal TH and a modest increase in TH within 6-12 h. Daily exposure to 6.5 kJ/m(2) over 30 min resulted in a gradual increase in epidermal TH, which reached 5-fold after five daily exposures. The increase in epidermal TH was accompanied by an increase in the TH oxidation products alpha-tocopherolquinone (TQ) and alpha-tocopherolhydroquinone (THQ). We also studied the effect of the prooxidant chemical tumor promoter benzoyl peroxide and the prooxidant azo initiators azobis(amidinopropane HCl) and azobis(2, 4-dimethylvaleronitrile). Topical application of these prooxidant chemicals acutely oxidized epidermal TH to TQ and THQ. Topical treatments with the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increased epidermal TH levels without producing a significant accumulation of TH oxidation products. The results indicate that UVB and tumor promoting chemicals all exert qualitatively different effects on epidermal TH status and that UVB and TPA trigger an adaptive response involving epidermal TH accumulation.
Carcinogenesis 2000 Feb
PMID:Effects of UV light and tumor promoters on endogenous vitamin E status in mouse skin. 1065 61

Many studies suggest that mutagenic/carcinogenic chemicals in the diet, like 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), may play a role in human cancer initiation. We have developed a method to quantify PhIP metabolites in human urine and have applied it to samples from female volunteers who had eaten a meal of cooked chicken. For this analysis, urine samples (5 ml) were spiked with a deuterium-labeled internal standard, adsorbed to a macroporous polymeric column and then eluted with methanol. After a solvent exchange to 0.01 M HCl, the urine extracts were passed through a filter, applied to a benzenesulfonic acid column, washed with methanol/acid and eluted with ammonium acetate and concentrated on a C(18) column. The metabolites were eluted from the C(18) column and quantified by LC/MS/MS. In our studies of human PhIP metabolism, eight volunteers were fed 200 g of cooked chicken containing a total of 27 microg PhIP. Urine samples were collected for 24 h after the meal, in 6 h aliquots. Although no metabolites could be found in urine collected from volunteers before eating the chicken, four major human PhIP metabolites, N:(2)-OH-PhIP-N:(2)-glucuronide, PhIP-N:(2)-glucuronide, 4'-PhIP-sulfate and N:(2)-OH-PhIP-N:3-glucuronide, were found in the urine after the chicken meal. The volunteers in the study excreted 4-53% of the ingested PhIP dose in the urine. The rate of metabolite excretion varied among the subjects, however, in all of the subjects the majority of the metabolites were excreted in the first 12 h. Very little metabolite was detected in the urine after 18 h. In humans, N:(2)-OH-PhIP-N:(2) glucuronide is the most abundant urinary metabolite, followed by PhIP-N:(2)-glucuronide. The variation seen in the total amount, excretion time and metabolite ratios with our method suggests that individual digestion, metabolism and/or other components of the diet may influence the absorption and amounts of metabolic products produced from PhIP.
Carcinogenesis 2000 Nov
PMID:Identification of urine metabolites of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine following consumption of a single cooked chicken meal in humans. 1106 69

Methods were developed for the efficient routine degradation and fractionation of ethylated and methylated DNA. Alkylated DNA was hydrolyzed by a neutral thermal method to yield 3- and 7- alkylpurines and O2-alkylcytosines. The partially apurinic DNA was separated from the bases by precipitation in 0.1 N HCl. Portions of the DNA precipitate were further hydrolyzed either by 0.1 N HCl to yield purine bases, or by enzymes to yield nucleosides and phosphotriesters. The chemical and enzymic digests were fractionated by a combination of high pressure liquid chromatography systems to yield quantitative estimates of the following products from methylated or ethylated DNA: 1-, 3-, and 7-alkyladenines, O2-alkylcytosines, 3-, O6-, and 7- alkylguanines and O2-, 3-, and O4-alkylthymines. N6-Alkyladenines, 1-alkylguanines and N2-alkylguanines were not detected and the 3- alkylcytosines were detected but not quantified. Phosphotriesters were estimated from the amounts of recovered alkyl phosphotriesters of thymidylyl (3'-5') thymidine. Using these methods, it was possible to account for 98, 81, 98, and 92% of the DNA bound alkyl groups obtained from DNA reacted with [14C]methyl methanesulfonate, [3H]ethyl methanesulfonate, N-[3H]-methyl-N-nitrosourea, and N-[14C]ethyl-N-nitrosourea, respectively. The methods described provide reproducible and quantitative methods of analysis for all the known methylated or ethylated products in a single DNA sample.
Carcinogenesis 1980 Jul
PMID:A comprehensive quantitative analysis of methylated and ethylated DNA using high pressure liquid chromatography. 1121 35

The effects of green tea on the metabolism of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) with emphasis on the formation of the detoxified glucuronides was studied. Two groups of 20 adult male and female Fischer 344 rats consumed 2% green tea or water for 6 weeks before being administered a single dose of 40 mg/kg body weight of [2-14C]IQ by oral gavage. Major metabolites in 24 h urine samples were separated by high-performance liquid chromatography (HPLC), including N-OH-IQ-N-glucuronide, 5-OH-IQ glucuronide and sulfate, IQ sulfamate and IQ itself. The structures of the main metabolites were established by mobility on the HPLC and by mass spectrometry. Sulfate esters and sulfamate were hydrolyzed by 0.1 N HCl for 15 min at 100 degrees C, yielding 5-OH-IQ and high levels of IQ. HPLC of the resulting product showed the N-OH-IQ-N-glucuronide and the 5-OH-IQ glucuronide, as well as IQ. The male and female rats drinking tea displayed a significantly higher (P < 0.05) excretion of the two major glucuronides. We conclude that intake of green tea increases the excretion of N-OH-IQ-N-glucuronide, a detoxified metabolite of the proximate carcinogen N-OH-IQ.
Carcinogenesis 2001 Jul
PMID:Urinary excretion of N-OH-2-amino-3-methylimidazo[4,5-f]quinoline-N-glucuronide in F344 rats is enhanced by green tea. 1140 54

4,4'-Methylenedianiline is used primarily as a chemical intermediate in the closed system production of isocyanates and polyisocyanates. These chemicals are used extensively in the manufacture of rigid polyurethane foams for thermal insulation and in the production of semiflexible polyurethane foams for automobile safety cushioning. The saturated isocyante of 4,4'-methylenedianiline [4,4'-methylene-bis(cyclohexylisocyanate)] is an intermediate in the production of light-stable, high-performance polyurethane coatings. 4,4'-Methylenedianiline is also a curing agent for epoxy resins and urethane elastomers, a dye intermediate, and a corrosion inhibitor. NTP 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 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1N 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 high dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower (P=0.006) than that in controls. Mean body weight was reduced in high dose female rats and in high dose male and female mice. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Compound-related nonneoplastic lesions of the thyroid in female rats included follicular cysts and hyperplasia. The incidence of thyroid follicular cell hyperplasia was elevated in high dose male and female mice. The incidences of thyroid neoplasms in the high dose groups were elevated compared with those of the control groups for both sexes of both species. Thyroid follicular cell carcinoma was increased in male rats (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%: P</=0.012). Follicular cell adenoma was increased in high dose female rats (0/47; 2/47, 4%; 17/48, 35%: P<0.001), in high dose male mice (0/47; 3/49, 6%; 16/49, 33%: P<0.001), and in high dose female mice (0/50; 1/47, 2%; 13/50, 26%: P<0.001) as compared with controls. In female rats, thyroid C-cell adenoma was also elevated in a dose-related manner (0/47; 3/47, 6%; 6/48, 13%, P</=0.029). Dose-related increases in nonneoplastic lesions were observed for male rats (nonspecific liver dilatation) and for male and female rats (fatty metamorphosis and focal cellular change). Liver degeneration was present in 80% of the low dose and 60% of the high dose male mice but was not found in the controls. Neoplastic nodules of the liver were observed at greater incidences (P</=0.002) for low and high dose male rats as compared with controls (control, 1/50, 2%; low dose, 12/50, 24%, P</=0.002; high dose 25/50, 50%, P<0.001). Hepatocellular adenoma was increased in a dose-related manner in dosed female mice (3/50, 6%; 9/50, 18%; 12/50, 24%, P<0.011). Hepatocellular carcinoma was observed in greater incidence in dosed male mice (10/49, 20%; 33/50, 66%, P<0.001; 29/50, 58%, P<0.001) and in high dose female mice (1/50, 2%; 6/50, 12%; 11/50, 22%, P=0.002). Male rats had a dose related increase in kidney mineralization. Nephropathy was increased in dosed mice of both sexes; renal papillary mineralization was greater in high dose male mice and female mice than in the controls. Other tumors that were elevated in dosed animals included adrenal pheochromocytomas in male mice (control, 2/48, 4%; low dose, 12/49, 24%, P</=0.006; high dose, 14/49, 29%; P</=0.001), alveolar/bronchiolar adenoma in female mice (1/50, 2%; 2/50, 4%; 6/49, 12%, P</=0.05) and malignant lymphomas in female mice (13/50,26%; 28/50, 56%, P=0.002; 29/50, 58%; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male (13/50,26&percnt;; 28/50, 56&percnt;, P=0.002; 29/50, 58&percnt;; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male rats (historical control 3/3,663), transitional-cell papillomas of the urinary bladder in female rats (historical control, 3/3,664, 0.08&percnt;; low dose, 2/50, 4&percnt;; high dose, 1/50, 2&percnt;) and granulosa cell tumors of the ovary in female rats (historical control, 11/3,642, 0.3&percnt;; low dose, 3/50, 6&percnt;; high dose, 2/50, 4&percnt;). Decreases in tumor incidences were observed for leukemia in male rats (control, 12/50, 24&percnt;; low dose, 6/50, 12&percnt;; high dose, 5/50, 10&percnt;, P=0.048) and alveolar or bronchiolar adenomas (combined) in male mice (12/49, 24&percnt;; 9/49, 18&percnt;; 3/49, 6&percnt;, P&le;0.011). Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly increased incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive
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PMID:NTP Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1275 Jul 45

An immunohistochemical differential staining of cancerous cells with anti-cytidine antibody after denaturation of nuclear DNA by acid hydrolysis with 2N HCl at 30 degree C for 20 min (DNA-instability test) has been used as a marker of malignancy. The test was applied to bioptic tissues of human gastric polyp assessed histopathologically as foveolar hyperplastic polyp (13 cases), mild (58 cases), moderate (86 cases), and severe (20 cases) dysplasia, and adenocarcinomas (14 cases). The serial sections of the same tissues were also subjected to immunohistochemical staining for Ki67, p53, DNA-fragmentation factor (DFF45), and basic fibroblast growth factor (bFGF). The DNA-instability test was positive in 14 (100%) adenocarcinoma cases, 20 (100%) severe dysplasia cases, 52 (60.5%) moderate dysplasia cases, and 12 (20.7%) mild dysplasia cases, indicating malignancy. All foveolar hyperplastic polyps were negative to the DNA-instability testing. Furthermore, the percentage of glands positive in the DNA-instability test steadily increased in going from mild (10%), to moderate (40%), to severe (100%) dysplasia, and adenocarcinoma (100%). All other biological markers tested in the present study showed significantly higher values in the adenoma glands, being positive to DNA-instability testing, irrespective of the dysplasia grade, as compared to those in the adenoma glands that were negative to DNA-instability testing. Furthermore, the former values were comparable to those in adenocarcinoma. These results indicate that cancer cell clones are already present at the adenoma stages showing a positive DNA-instability test, enhanced proliferative activity, p53 mutation, induction of DFF45 and bFGF. These factors allow cancer cell proliferation, producing heterogeneous subclones due to DNA-instability, enhancing their survival by escaping apoptosis, and providing abundant nutrients during the early-stage progression of gastric cancer. Based on these findings, we herein propose the concept of "procancer" (as opposed to "pre-cancer") as being a unique stage during the course of carcinogenesis and cancer progression. We designate the term to cancer clones at the very early stages of malignant progression that do not show distinguishable morphological atypia but do show positive DNA-instability testing and positive staining for various biomarkers such as Ki67, p53, DFF45, and bFGF. We also define the abnormal positive staining of these biomarkers, including the DNA-instability test as "functional atypia", compared to the ordinary morphological atypia.
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PMID:Detection of cancer clones in human gastric adenoma by increased DNA-instability and other biomarkers. 1277 6


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