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)

Male rats were treated with [ring-3H]N-acetyl-2-aminofluorene and sacrificed at different periods of time after a single i.p. dose. Chromatin was isolated from liver homogenates and treated with RNAse and proteinase K. The resulting crude DNA was purified as the N-hexadecyl-N-trimethylammonium salt. The amounts of 2-aminofluorene and N-acetyl-2-aminofluorene bound to carbon-8 of guanine were determined in the DNA via acid hydrolysis and high pressure liquid chromatography of the hydrolysate. These two major interaction products of the carcinogen decreased rapidly during the first 2 weeks but in the second 2 weeks the decrease of both interactions was much smaller and approximately 15% of the amount that was bound after 24 h remained persistently bound to the DNA. Differences in liver DNA binding after 24 h were observed between male rats of the strain R-Amsterdam (Wistar-related) and Sprague Dawley males. At equal dose levels of N-acetyl-2-aminofluorene, liver DNa of Sprague Dawley rats contained 1/3 of the amount of N-(guanin-8-yl)-2-aminofluorene and 1/2 of the amount of N-(guanin-8-yl)-N-acetyl-2-aminofluorene present in liver DNA of the R-Amsterdam strain.
Carcinogenesis 1981
PMID:Partial persistency of 2-aminofluorene and N-acetyl-2-aminofluorene in rat liver DNA. 728 80

According to the bile salt theory of colon carcinogenesis, therapeutic agents which increase the delivery of bile salts to the large intestine may promote colon cancer. The possibility that aluminium hydroxide (Aludrox), a bile salt binding agent, might facilitate colon carcinogenesis in vivo was tested experimentally, using the dimethylhydrazine (DMH)-induced rat colon cancer model. 48 Wistar rats were randomly allocated to 1 of 3 groups, all fed the same standard diet. Two groups received a course of ten weekly DMH injections. One was allowed fresh drinking water ad libitum whilst the other received Aludrox in their drinking water. A third group received weekly saline injections plus Aludrox in their drinking water. After 1 year's observation, there were no significant differences between the groups of DMH-injected rats given drinking water with or without Aludrox in respect of survival, necropsy incidence of primary or metastatic colon cancer, or in the total number of colon tumours per group. The results provide reassurance that Aludrox does not promote colon cancer and tend to contradict the bile salt theory of colon carcinogenesis.
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PMID:Experimental evidence against the bile salt theory of colon carcinogenesis. 729 76

The responses of male noninbred rat colonic epithelial ornithine decarboxylase (EC 4.1.1.17) (ODC) and S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) (SAMD) activities following topical administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or bile salts were studied. A single intrarectal installation of 13 mumol of MNNG resulted in a significant (p < 0.001) 20-fold peak ODC activity after 4 hr, with a prompt return to control levels by 12 hr. Stimulation of SAMD activity was less pronounced but significant (p < 0.01), with a broad 2-fold peak over controls. No significant responses of colonic epithelial enzyme activities were detected following a single intrarectal instillation of N-methyl-N'-nitroguanidine, a noncarcinogenic and nonmutagenic metabolite of MNNG, at a dose equimolar to that of MNNG. Bile salts significantly (p < 0.001) induced ODC with almost the same kinetic pattern as that observed after MNNG administration in the following order: sodium deoxycholate > sodium chenodeoxycholate > sodium cholate. Activations of SAMD were similar for these 3 bile salts. Glycine- or taurine-conjugated deoxycholate showed ODC and SAMD enzyme activations similar to that of nonconjugated deoxycholate. No significant enzyme response was seen after sodium dehydrocholate treatment. Stimulation of activities of both enzymes was directly dependent on bile salt dose. Induced ODC and SAMD activities were principally localized in colonic epithelium. Deoxycholate-stimulated enzyme activities were significantly inhibited by cycloheximide. Enzyme stimulations by active compounds were accompanied by morphological changes such as mucosal cell degeneration, mucus depletion, submucosal congestion, and punctate hemorrhage, followed by submucosal leukocytic cellular infiltration. These data support the concept that initiating and promoting events may be involved in colon carcinogenesis.
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PMID:Early induction of rat colonic epithelial ornithine and S-adenosyl-L-methionine decarboxylase activities by N-methyl-N'-nitro-N-nitrosoguanidine or bile salts. 744 10

o-Phenylphenol (OPP) and its sodium salt, sodium o-phenylphenate are broad spectrum fungicides and disinfectants with widespread usage. Both chemicals have been reported to induce cancer in the kidney and urinary bladder of Fischer 344 rats. Recently it has been proposed that the metabolic activation of OPP occurs via a two-step process involving the cytochrome P450-mediated formation of phenylhydroquinone (PHQ) in the liver and a prostaglandin H synthase-mediated oxidation of PHQ to phenylbenzoquinone (PBQ) in the urinary tract. In order to further investigate the metabolic activation and genotoxic effects of OPP, we have investigated the ability of PHQ and PBQ to induce micronuclei and mutations at the HGPRT locus in a prostaglandin H synthase-containing V79 Chinese hamster lung fibroblast cell line. In arachidonic acid-supplemented V79 cells, PHQ induced a significant increase in micronuclei whereas no increase was observed in cells in the absence of arachidonic acid supplementation. Immunofluorescent labeling of centromeric proteins with the CREST antibody indicated that the arachidonic acid-dependent induction of micronuclei by PHQ was due almost entirely to micronuclei containing whole chromosomes which had failed to segregate properly during mitosis. The induction of micronuclei by PHQ was significantly inhibited by treatment of the cells with indomethacin, aspirin, ascorbic acid, dithiothreitol and reduced glutathione supporting a role for prostaglandin H synthase in the genotoxic effects of PHQ. No increase in 6-thioguanine-resistant cells was observed in cells treated with PHQ or PBQ. This arachidonic acid-dependent conversion of PHQ to a genotoxic species is consistent with the hypothesis that a prostaglandin H synthase-mediated activation of PHQ may be involved in OPP- and SOPP-induced urinary tract carcinogenesis and also suggests that the induction of aneuploidy may play an important role in OPP-induced tumorigenesis.
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PMID:Genotoxic effects of the o-phenylphenol metabolites phenylhydroquinone and phenylbenzoquinone in V79 cells. 752 18

The O6-methylguanine-DNA methyltransferase (MGMT) repairs mutagenic and carcinogenic O6-alkylguanine in DNA by accepting stoichiometrically the alkyl group from the base. Although the mouse MGMT is larger than the human protein because of an additional tetrapeptide sequence, these proteins are 70% homologous. Recombinant MGMTs of the human, the mouse and a mouse mutant with the tetrapeptide deleted were purified to homogeneity from Escherichia coli. The N-terminal amino acid sequences of these proteins are identical to those predicted from the nucleotide sequences, and their molecular masses determined by SDS-PAGE agreed with the predicted values. However, the observed isoelectric points of 9.3, 9.2 and 9.3, for the human, mouse and mutant mouse proteins respectively were significantly different from the values, 8.09, 7.47 and 7.49 calculated from the amino acid composition. The extinction coefficients E280 nm1% of human, mouse and mutant mouse protein were calculated from amino acid composition to be 18.2, 11.1 and 11.3 respectively. These values agree fairly well with calculated values. Human and wild-type mouse MGMTs react with the alkylated base in a synthetic DNA substrate poly(dC, dG, m6dG) with comparable second-order rate constants of 2.2 x 10(8) and 3.7 x 10(8) l/M/min at 37 degrees C respectively and were inactivated by O6-benzylguanine at similar rates. The initial reaction rate (Kin) and rate of inactivation (kinact) constants for reaction with the base were calculated to be 1.8 x 10(-4) M and 1.4 x 10(-3)/s for the human protein, 2.3 x 10(-4) M and 1.1 x 10(-3)/s for the wild-type mouse protein, and 2.1 x 10(-4) M and 1.4 x 10(-3)/s for the mutant mouse protein respectively. The MGMTs were inactivated to the extent of 55-65% after heating at 50 degrees C in 20 mM Tris-HCl, pH 8.0, 1 mM EDTA, 1 mM DTT and 10% glycerol. However, in the presence of DNA (200 micrograms/ml), only 25-35% of the protein was inactivated. Both DNA and RNA inhibited all three enzymes in a concentration-dependent fashion, although DNA was a better inhibitor than RNA. High salt (0.2 M NaCl) inhibited human MGMT by 80%, while the wild-type and the mutant mouse MGMTs were inhibited by 55%. The human protein had higher affinity for binding to duplex DNAs than the mouse proteins. Immunoprecipitation (69%) and affinity constant (19.4 nM) of human MGMT with a human-specific monoclonal antibody 4.A1 significantly discriminated the human protein from either of the mouse proteins.
Carcinogenesis 1995 Feb
PMID:A comparative study of the biochemical properties of human and mouse recombinant O6-methylguanine-DNA methyltransferases. 753 16

Most countries with adequate statistical infrastructure have registered declines in gastric cancer mortality and incidence rates. Such a trend is dominated by the most frequent variant, namely the so-called intestinal type of adenocarcinoma, usually ulcerated and occupying predominantly the antrum and the antrum-corpus junction. This variant is considered the endstage of a prolonged precancerous process with gradual progression from (a) chronic active gastritis to (b) multifocal atrophic gastritis to (c) intestinal metaplasia, first resembling the phenotype of the small intestine and later that of the colon, to (d) dysplasia and (e) finally to invasive carcinoma. Major trends in dietary habits, namely lower intake of salt and increased and more frequent consumption of fresh fruits and vegetables, have been linked to the decline. In parallel with those trends, improved sanitation and more adequate housing may be responsible for the declining rates of infection with Helicobacter pylori, the major cause of chronic active gastritis. A decline in the frequency of papillary adenocarcinoma of the oxyntic mucosa, associated with the pernicious anaemia syndrome, appears to have taken place much earlier. Although the frequency of the pernicious anaemia syndrome seems to have remained at similar levels, its complications in terms of papillary adenocarcinoma have decreased in populations of northern European extraction. This may be related to time trends in dietary habits. The secular decline in diffuse carcinoma has been either of much less magnitude or non-existent. Few clues are available on this tumour variant. It is somewhat predominant in women, in subjects of blood group A phenotype, and less frequent in older subjects. Cell lines derived from diffuse carcinomas lack functional calcium dependent adhesion molecules ("cadherins"). Recent increases in incidence rates have been registered for adenocarcinoma of the gastric cardia. This increase parallels that of lower oesophageal adenocarcinoma, frequently linked with Barrett's oesophagus, reflux oesophagitis, a history of duodenal ulcer and gastric hypersecretion. New developments in molecular biology are being used to study the process of gastric carcinogenesis. There is hope that specific molecular alterations may provide better understanding of the different variants of gastric carcinoma and their secular trends.
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PMID:Gastric cancer. 753 41

Chlorophyll and chlorophyllin, a water-soluble salt of chlorophyll, have been reported to inhibit carcinogen-DNA binding and exert antimutagenic activity for some carcinogenic heterocyclic amines and aflatoxins. In the present experiment, the possible inhibitory effects of chlorophyllin on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) carcinogenicity were investigated. Female F344 rats were administered both PhIP, 0.02% in the diet, and chlorophyllin, 1%, in the diet (group 1), or either PhIP (group 2) or chlorophyllin (group 3) alone for 54 weeks. The incidence of mammary adenocarcinomas induced by PhIP was reduced by chlorophyllin co-administration from 40% (8/20 rats) to 15% (3/20). While the difference was not statistically significant, the multiplicity of adenocarcinomas was significantly (P < 0.05) reduced by chlorophyllin co-administration from 0.50 per animal to 0.15. On the other hand, incidence of colon adenomas was slightly, but not significantly, increased from 10% to 20%. Neither mammary nor colon adenocarcinomas were observed in group 3. Thus, chlorophyllin reduced PhIP mammary carcinogenesis, suggesting that chlorophyllin is an effective chemopreventor when ingested simultaneously with the carcinogen.
Carcinogenesis 1995 Sep
PMID:Inhibitory effect of chlorophyllin on PhIP-induced mammary carcinogenesis in female F344 rats. 755 83

The overview of apoptosis presented here emphasizes cell deletion in the immune system, with particular reference to T- and B-lymphocyte development, and the in vivo and in vitro senescence of human neutrophils. Some biochemical criteria that are used to identify apoptotic cells are described. Pitfalls in using agarose gel electrophoresis as the sole method for the identification of apoptotic cells are discussed. There are multiple modes of cell death that can be identified at the morphologic level. Thus the central role of microscopic methods, and in particular, electron microscopy, as an important tool in the study of cell death mechanisms, is presented. Apoptosis has a protective role against disease and could, a priori, have an important role in either the initiation or progression of cancer. Two paradoxes concerning the relationship of tumor aggressiveness at the clinical level to mitotic activity have been explained by an evaluation of apoptotic index. In the first case, basal cell carcinomas grow slowly but show a high rate of mitosis. Here, the apoptotic rate is quite high, but just below the mitotic rate, thereby accounting for the slow rate of growth. A second instance is follicular lymphoma, which has a low rate of mitosis that is less than that described for reactive germinal centers. However, apoptosis is markedly reduced in follicular lymphomas compared with that seen in reactive germinal centers, thus providing an explanation for the progressive growth of the follicle. We present a brief description of recent work from our laboratory that indicates that apoptosis may play an important role in colon carcinogenesis. We have shown that sodium deoxycholate, the particular bile salt present in highest concentration in the colon, induces apoptosis in the goblet cells of the human colonic mucosa in an in vitro assay. The intriguing finding is that cells of the normal-appearing mucosa of colon cancer patients are resistant to bile salt-induced apoptosis. This suggests a novel hypothesis about the etiologic role of bile salts in colon cancer. The chronic presence of bile salts that accompany a high-fat diet could select for apoptosis-resistant epithelial cells in the colon over time. Thus, a resistance-to-apoptosis bioassay may prove useful as an intermediate biomarker for determining which individuals are at high risk for colon cancer.
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PMID:Role of apoptosis in biology and pathology: resistance to apoptosis in colon carcinogenesis. 757 Oct 81

Several lines of evidence from our laboratory and others indicate that epigenetic alterations in protein kinase C (PKC) are involved in colonic carcinogenesis in both man and experimental animals. Furthermore, bile salts, known activators of PKC, have also been implicated in colonic tumor development. Recently, however, our laboratory has demonstrated that, whereas dietary cholic acid increased the occurrence of azoxymethane (AOM)-induced rat colonic tumors, ursodeoxycholic acid was associated with a significant protective effect. In the present studies, we therefore examined changes in PKC isoforms that accompanied AOM-induced tumor formation and investigated whether the chemopromotional and/or chemopreventional actions of these supplemental dietary bile salts involved changes in specific isoforms of PKC. Rats treated with vehicle (saline) or AOM and maintained on bile salt unsupplemented or supplemented diets were used to isolate control colonocytes and carcinogen-induced tumors, which were then subjected to subcellular fractionation. The homogenates and subcellular fractions were then probed for individual PKC isoforms by quantitative Western blotting using isoform-specific antibodies. Normal rat colonocytes expressed PKC-alpha, -beta II, -delta, -epilson, and -zeta. AOM, in unsupplemented or cholate-supplemented groups, caused significant down-regulation of PKC-alpha, -delta and -zeta and up-regulation of PKC-beta II, while increasing particulate PKC-alpha, -beta II, and -zeta in carcinogen-induced tumors compared to normal colonocytes. Dietary supplementation with ursodeoxycholic acid, in marked contrast to these groups, prevented the changes in the subcellular distributions of PKC-alpha, -beta II, and -zeta, and preserved the expression of PKC-zeta in AOM-induced tumors. These studies suggest that changes in specific isoforms of PKC (particularly, PKC-alpha, -beta II, -delta, and/or -zeta) are involved in colonic malignant transformation in the AOM model but do not account for the chemopromotional actions of cholic acid in this model. Furthermore, the ability of ursodeoxycholic acid to block AOM-induced increases in particulate PKC-alpha, -beta II, and -zeta, and/or inhibit down-regulation of PKC-zeta, may contribute to the chemopreventive effects of this bile acid.
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PMID:Mechanism of action of chemoprotective ursodeoxycholate in the azoxymethane model of rat colonic carcinogenesis: potential roles of protein kinase C-alpha, -beta II, and -zeta. 758 85

Sodium saccharin administered at high doses to male rats beginning after 5 weeks of age produces mild urothelial hyperplasia but does not result in a significant increase in incidence of bladder cancer unless it is administered after an initiating agent. However, if it is administered in a two-generation bioassay, a significant incidence of bladder tumors is produced. The hyperplastic and tumorigenic effects are inhibited by co-administration with high doses of NH4Cl. The present experiment was designed to evaluate the effects of another sodium salt, sodium ascorbate, administered through the neonatal time period. Sodium saccharin administered as 5% of the diet produced urothelial hyperplasia and increased labeling index, and this was inhibited by co-administration with 1.23% NH4Cl. Four doses of sodium ascorbate was evaluated. The lowest dose, 0.91%, was without effect on the urinary tract. A slight effect (not statistically significant) was observed at a dose of 2.73%, and a significant proliferative response was detected at 4.56 and 6.84%. Recent studies suggest that a calcium phosphate-containing amorphous precipitate forms in the urine of rats fed high doses of sodium saccharin, producing cytotoxicity of the urothelium and consequent regenerative hyperplasia. This precipitate was observed in the present experiment in the rats administered the high dose of sodium saccharin or the higher doses of sodium ascorbate. Formation of this precipitate and induction of urothelial proliferation were inhibited by co-administration of NH4Cl, but somewhat higher doses of ammonium chloride were required for doses of sodium ascorbate compared to sodium saccharin. These results demonstrate that sodium ascorbate administered through the neonatal time period of the male rat produces urothelial hyperplasia in the dose responsive manner, with a no-effect level of 0.91% of the diet. The formation of the calcium phosphate-containing amorphous precipitate and urothelial proliferation were inhibited by co-administration with NH4Cl.
Carcinogenesis 1995 Nov
PMID:Effects of sodium ascorbate, sodium saccharin and ammonium chloride on the male rat urinary bladder. 758 94


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