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)

Short-term assays in vivo have suggested that hickory smoke condensate (HSC), a food flavouring, might have tumour-initiating and/or promoting activities in the glandular stomach of the rat. In the present study, the modifying effects of HSC on glandular stomach carcinogenesis after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride (MNNG salt) were investigated in male Wistar rats. Animals were given MNNG solution (100 ppm) as drinking water and simultaneously fed the diet supplemented with 5% sodium chloride for 8 wk. Matched negative controls received neither MNNG nor sodium chloride. Rats were then fed a basal diet and given HSC solution (1 or 3%) or tap water for the following 32 wk. During the experimental period, treatment with MNNG salt and administration of HSC both brought about growth retardation although the final body weight of rats was comparable between groups. Only two rats treated with MNNG salt followed by 1% HSC developed adenocarcinoma of the stomach. HSC treatment appeared to increase the number of rats with preneoplastic hyperplasias and/or adenocarcinomas in both the fundic and pyloric mucosa, although not to a statistically significant extent. HSC administration significantly increased malondialdehyde levels in the urine and gastric mucosa, the former in a dose-dependent manner. The results suggest that HSC has little, if any, promoting effect on two-stage glandular stomach carcinogenesis in rats when given during the post-initiation phase. However, the tumour co-initiating effects of HSC require further clarification.
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PMID:Effects of hickory smoke condensate on gastric carcinogenesis in Wistar rats after treatment with N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride. 844 84

Chromium metal salts are considered to be human carcinogens, especially the salts of low solubility. Lead chromate, a highly insoluble chromium metal salt, has been shown to be tumorigenic, genotoxic and clastogenic. In this study, the roles of particle-cell contact, particle dissolution and particle uptake in the clastogenic activity of lead chromate were investigated. Using Pb51CrO4 it was found that lead chromate particles (1.2 microns mean diameter, -28 mV surface charge) were slightly soluble in water; solubility increased 2-fold when particles were incubated in culture medium, but was not increased further by the addition of serum. The extracellular concentration of chromium increased 7-fold when lead chromate was incubated in the presence of Chinese hamster ovary (CHO) cells compared with culture medium alone. The intracellular concentration of ionic chromium increased in a dose-dependent manner following exposure of CHO cells to clastogenic doses of lead chromate reaching estimated levels as high as 1.2 mM per cell. Treatment of cells with lead chromate particles in the presence of a nontoxic dose of vitamin C blocked uptake of ionic chromium and eliminated the clastogenic activity of the particles. Transmission electron microscopy showed that lead chromate particles were internalized by CHO cells in phagocytic vacuoles in as little as 1 h; internalization was unaffected by co-treatment with vitamin C. It was demonstrated that particle-cell contact was required for lead chromate-induced clastogenesis. These data show that although phagocytic particle uptake occurs, particle-cell contact and extracellular dissolution are responsible for the clastogenic activity of lead chromate. These data also demonstrate that the genotoxicity of particulate hexavalent chromates can be blocked by vitamin C.
Carcinogenesis 1993 Mar
PMID:Inhibition of lead chromate clastogenesis by ascorbate: relationship to particle dissolution and uptake. 845 19

Rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD) inactivates circulating steroid hormones and is involved in polycyclic aromatic hydrocarbon (PAH) carcinogenesis. It is the only HSD of known structure in the aldo-keto reductase (AKR) superfamily and may provide a paradigm for other mammalian HSDs in this family. The structure of the 3 alpha-HSD.NADP+ binary complex has been determined at 2.7 A resolution and refined to a crystallographic R-factor of 23.4% with good geometry. The model is similar to other binary complexes in the AKR superfamily in that NADP+ binds at the C-terminal end of an alpha/beta barrel. However, it is unique in that NADP+ is bound in two alternate conformations, probably because of the lack of a salt-linked "safety belt" over the pyrophosphate bridge. The structure supports a previously proposed catalytic mechanism for carbonyl reduction in which Tyr 55 is the general acid, and its effective pKa is lowered by the adjacent Lys 84. We present evidence that the structurally distinct short-chain dehydrogenase/reductase (SDR) superfamily may have convergently evolved a similar catalytic mechanism. Insight into substrate binding is offered by a crystal packing contact in which a neighboring molecule inserts a tryptophan residue (Trp 227) into an apolar cleft in 3 alpha-HSD. This cleft is proximal to the bound NADP+ cofactor and contains a surface of apolar residues (Leu 54, Trp 86, Leu 122, Phe 128, Phe 129, Leu 137, Phe 139), making it a likely candidate for the substrate-binding site. Thus, in forming this crystal contact, Trp 227 may mimic a portion of a bound steroid. In addition, we propose that a water molecule in the active site indicates the position of the hydroxyl oxygen in a 3 alpha-hydroxysteroid substrate. Knowledge of the position of this water molecule, combined with the stereochemistry of hydride transfer, suggests that the alpha face of a bound steroid will be oriented toward the side of the apolar cleft containing Trp 86.
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PMID:Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+. 871 59

Bacterial infections traditionally have not been considered major causes of cancer. Recently, however, bacteria have been linked to cancer by two mechanisms: induction of chronic inflammation and production of carcinogenic bacterial metabolites. The most specific example of the inflammatory mechanism of carcinogenesis is Helicobacter pylori infection. H. pylori has been epidemiologically linked to adenocarcinoma of the distal stomach by its propensity to cause lifelong inflammation. This inflammation is in turn thought to cause cancer by inducing cell proliferation and production of mutagenic free radicals and N-nitroso compounds. H. pylori is the first bacterium to be termed a definite cause of cancer in humans by the International Agency for Research on Cancer. Mutagenic bacterial metabolites are also suspected to increase risk for cancer. This model is best exemplified in colon cancer. Bile salt metabolites increase colonic cell proliferation. Exogenous compounds such as rutin may be metabolized into mutagens by resident colonic flora. Moreover, Bacteroides species can produce fecapentaenes, potent in vitro mutagens, in relatively high concentrations. In vivo data on human carcinogenesis by bacterial metabolites, however, are inconsistent. Local bacterial infections may also predispose to nonnodal lymphomas, although the mechanisms for this are unknown. Gastric lymphomas and immunoproliferative small intestinal disease have been most strongly linked to underlying bacterial infection. Because bacterial infections can be cured with antibiotics, identification of bacterial causes of malignancy could have important implications for cancer prevention.
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PMID:Bacterial infection as a cause of cancer. 874 96

The potentially protective role of chlorophyllin, the sodium and copper salt of chlorophyll a against the initiation and promotion stages in carcinogenesis was studied by in vitro short-term assays. Chlorophyllin showed a dose-dependent suppressive effect on 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indol (Trp-P-1)-induced umu C gene expression of Salmonella typhimurium (TA 1535/pSK 1002) in the presence of metabolizing enzyme mixture. The similar inhibitory effect of chlorophyllin was detected in mitomycin C (MMC)-dependent umu C gene expression in the absence of metabolizing enzyme mixture. Furthermore chlorophyllin also exhibited a dose-dependent inhibition on 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity of 3T3 fibroblast cells at the same concentrations. However, when chlorophyll a isolated from Japanese tea leaves was applied on the same assay systems as a comparative experiment, chlorophyll a showed much weaker activity compared with that of chlorophyllin. The significance of this finding is discussed from the viewpoint of the protective role of chlorophyllin against carcinogenesis.
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PMID:Suppressive effects of chlorophyllin on mutagen-induced umu C gene expression in Salmonella typhimurium (TA 1535/pSK 1002) and tumor promoter-dependent ornithine decarboxylase induction in BALB/c 3T3 fibroblast cells. 883 Aug 2

Carcinomas of the gastrointestinal tract (GI) are among the most common malignancies with regard to their incidence and mortality. Nutritional factors play an important role in the tumor development. The strength of their influence varies with the localization in the GI tract. Epidemiological studies focusing on GI cancer incidence or mortality as an endpoint necessitate large numbers of subjects to achieve significant results. Generally, a low energy and fat intake and a high intake of antioxidative vitamins (vitamin C, E, beta-carotene) and secondary plant metabolites (especially polyphenols) appear to be protective in GI carcinogenesis. Moderate drinking of alcohol and increased consumption of whole grain products, as opposed to highly refined carbohydrates, may help to reduce the risk of colon cancer. The recommended type of diet is low in fat, especially in saturated fatty acids, includes monounsaturated fatty acids, and includes moderate amounts of polyunsaturated fatty acids (no more than 10% of calories). Moderate consumption of salt and of highly salted, smoked, and barbecued foods should be encouraged. Obesity should be avoided by trying to match energy intake with expenditure while increasing physical activity levels. The mechanisms by which nutritional factors act especially on molecular events still remain to be examined. The use of molecular biomarkers will help us better understand cancer development as well as the role and significance of nutritional factors in this process.
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PMID:Basis and consequences of primary and secondary prevention of gastrointestinal tumors. 889 41

The practice of medicine-both past and present-often involves the prescription of specific foods (almost always plants) or their potent derivatives, to treat a wide spectrum of illnesses. Foods that have been ascribed healing properties include the Cruciferae, the allium family, celery, cucumber, endive, parsley, radish and legumes. Review of the epidemiological data, including both cohort and case-control studies, of all cancer sites strongly suggests that plant foods also have preventive potential and that consumption of the following groups and types of vegetables and fruits is lower in those who subsequently develop cancer: raw and fresh vegetables, leafy green vegetables, Cruciferae, carrots, broccoli, cabbage, lettuce, and raw and fresh fruit (including tomatoes and citrus fruit). Other data suggest that foods high in phytoestrogens, particularly soy (which contains isoflavones), or high in precursor compounds that can be metabolized by gut bacteria into active agents, particularly some grains and vegetables with woody stems (which contain precursors to lignans), are plausibly associated with a lower risk of sex-hormone-related cancers. The human evidence for these latter associations is not strong. There are many biologically plausible reasons why consumption of plant foods might slow or prevent the appearance of cancer. These include the presence in plant foods of such potentially anticarcinogenic substances as carotenoids, vitamin C, vitamin E, selenium, dietary fibre (and its components), dithiolthiones, isothiocyanates, indoles, phenols, protease inhibitors, allium compounds, plant sterols, and limonene. Phytoestrogens are also derived from some vegetables and berries as well as grains and seeds. Most of the data for the observations on the anticarcinogenic potential of all of these compounds have come from animal and in vitro studies. At almost every one of the stages of the cancer process, identified phytochemicals are known to be able to alter the likelihood of carcinogenesis-occasionally in a way that enhances risk but usually in a favourable direction. For example, glucosinolates and indoles, thiocyanates and isothiocyanates, phenols, and coumarins can induce a multiplicity of phase II (solubilizing and usually inactivating) enzymes; ascorbate and phenols block the formation of carcinogens such as nitrosamines; flavonoids and carotenoids act as antioxidants, essentially disabling the carcinogenic potential of specific compounds; lipid-soluble compounds such as carotenoids and sterols may alter membrane structure or integrity; some sulphur-containing compounds suppress DNA and protein synthesis; carotenoids can suppress DNA synthesis and enhance differentiation; and phytoestrogens compete with estradiol for estrogen receptors in a way that is generally antiproliferative. Consumption of diets low in plant foods results in a reduced intake of a wide variety of those substances that can plausibly lower cancer risk. In the presence of a diet and lifestyle high in potential carcinogens (whether derived from fungal contamination, cooking or tobacco) or high in promoters (such as salt and alcohol), overall risk of cancer at many epithelial sites is elevated. Plant foods appear to exert a general risk-lowering effect; the patterns of exposure to cancer initiators and promoters and of genetic susceptibility may determine the variations in the site-specific risks of cancer seen across populations.
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PMID:Vegetables, fruit and phytoestrogens as preventive agents. 892 20

Cadmium is carcinogenic in humans and rodents. Although extensive evidence indicates that the toxicity and genotoxicity of Cd is ameliorated by binding to cysteine clusters in metallothionein (MT), the factors governing Cd release at intracellular target sites remain unknown. Nitric oxide is a pollutant gas and an important intercellular messenger in the inflammatory immune response. When growing Chinese hamster ovary cells were treated for 24 h with 0.5, 0.75, or 1.0 mM CdCl2 followed by a 1-h exposure to 1.0, 1.5, or 2.0 mM 1,1-diethyl-2-hydroxy-2-nitrosohydrazine (DEA/NO), an NO-generating sodium salt, NO enhanced Cd-induced inhibition of colony forming ability without affecting Cd-induced cytolethality. In experiments designed to determine whether NO acts by displacing Cd from cellular MT, cells treated with 2.0 mM CdCl2 followed by 1.5 or 3.0 mM DEA/NO exhibited 29 and 38% reductions, respectively, in the amount of Cd bound to MT. When purified rat liver MT was used to further characterize NO-induced release of Cd from MT, dose-related increases in Cd displacement were observed at DEA/NO concentrations between 0.1 and 0.5 mM, and a plateau was reached at 3 mol of Cd displaced/mol of MT at higher DEA/NO concentrations. Compared to cells exposed to Cd or DEA/NO alone, cells treated with Cd followed by DEA/NO also exhibited a transient 2-3-fold decrease in c-myc proto-oncogene expression. Taken together, our results support the hypothesis that NO mediates Cd release from MT in vivo and suggest that intracellular generation of free Cd may induce DNA damage and force cells into a period of growth arrest. Such findings may have particular relevance with regard to the etiology of Cd-induced carcinogenesis in human populations.
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PMID:Evidence that nitric oxide enhances cadmium toxicity by displacing the metal from metallothionein. 892 12

The customary salting and pickling of fish in high risk gastric cancer regions were modeled to explore the relevant causative chemicals. The fish Sanma hiraki was treated with sodium chloride and sodium nitrite at pH 3. Previously, it had been found that an extract of the treated fish was mutagenic in Salmonella typhimurium TA 1535 without S9 and also that it induced glandular stomach cancer upon gavage to rats. We now demonstrate that the mutagenicity was enhanced by preincubation of the raw meat for several days before salt-nitrite treatment. HPLC techniques showed that three mutagens were present in the fish extract. One of the mutagens was found to be stable over the pH range of 1.0-9.0. This mutagen was purified by silica gel solid phase extraction, followed by a series of reverse phase HPLC steps, and was characterized by low and high resolution MS, NMR, and FT-IR. While N-nitroso compounds were generally believed to be associated with gastric carcinogenesis, it was unexpectedly found that the mutagen has the novel structure 2-chloro-4-methylthiobutanoic acid (CMBA). Based on the structure, it seemed likely that methionine might be the precursor, and this was, indeed, proven. Both salt and nitrite are essential factors for forming this mutagen. The yield of CMBA was linear for chloride concentrations from 0 to 800 mM NaCl. Of 20 amino acids reacted with nitrite and chloride at pH 3, only methionine generated a mutagen for S. typhimurium TA 1535. Tryptophan gave a product mutagenic in S. typhimurium TA 100 and TA 98, but not TA 1535, and in the case of tyrosine, the mutagen was active only for TA 100. These results suggest an important role for salt in gastric carcinogenesis and provide new approaches for exploring the formation of mutagens/carcinogens for specific target organs.
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PMID:Gastric carcinogenesis: 2-chloro-4-methylthiobutanoic acid, a novel mutagen in salted, pickled Sanma hiraki fish, or similarly treated methionine. 892 17

Stomach cancer remains a common type of cancer, though its incidence has been halved in the last forty years. It is unevenly distributed throughout the world. In France, it holds fifth place among cancers and there are 8700 new cases each year. Helicobacter pylori infection, a high salt intake as well as an inadequate diet take part in the first stages of carcinogenesis. Later on, nitrates and nitrites, polycyclic hydrocarbons, alcohol, tobacco and bilc acids are incriminated. The protective role of vegetables and fruit has been well established. The protective role of vitamin C and beta-carotene is currently undergoing evaluation in subjects suffering from precancerous conditions such as dysplasia and incomplete intestinal metaplasia. The development of a vaccine against Helicobacter pylori induced infection also represents an important goal.
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PMID:[Epidemiology and etiology of malignant gastric tumors]. 918 59


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