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

Altered transport of nuclear RNA sequences is an early response to carcinogens. Nuclear envelopes (NE) were isolated and assayed for nucleoside triphosphatase activity (NTPase), on the premise that this enzymatic activity participates in RNA transport. A common feature of the action of five different carcinogens (thioacetamide, 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, dimethylnitrosamine, and aflatoxin B1), at low doses without significant toxicity, was to increase NE NTPase activity and to increase RNA transport, as assessed by the appearance of rapidly labeled RNA in the cytoplasm and by in vitro assay. The increases in NTPase were specific for the NE fraction, and early toxic effects of higher doses initially masked the increases. The induced increases in NE NTPase were long-lived. In contrast, increases in NE NTPase were observed only during the regenerative phase of CCl4 intoxication; the CCl4-induced increase was short-lived and returned promptly to control levels. These changes in NTPase activity were not associated with parallel changes in phosphorylation/dephosphorylation of NE proteins. Increases in NE NTPase and alterations in RNA transport, without attendant nuclear replication, may relate to altered nuclear RNA restriction. This change in a regulatory phenomenon may make these cells more susceptible to further modification, potentially playing a role in the initiation phase of carcinogenesis.
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PMID:Increased nucleoside triphosphatase activity of rat liver nuclear envelope is associated with hepatocarcinogen exposure. 620 70

Adult male Fischer rats were exposed to a necrogenic dose (200 mg/kg) of diethylnitrosamine or to nonnecrogenic doses of N-methyl-N-nitrosourea, 1,2-dimethylhydrazine, or benzo(a)pyrene following partial hepatectomy or sham hepatectomy. This treatment by itself led to no hepatocellular carcinomas by 8 to 18 months, except in animals given N-methyl-N-nitrosourea, which showed a 30% incidence by 12 months. With each treatment regimen, exposure to dietary 2-acetylaminofluorene for 2 weeks coupled with partial hepatectomy or the administration of a necrogenic dose of CCl4, was associated with an incidence of 68 to 94% of cancer at 8, 12, or 18 months, depending upon the initiating carcinogen used. Appropriate controls showed either no hepatocellular carcinoma or a much lower incidence. It is concluded that the 2-week exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or the administration of CCl4 has a strong promoting effect on liver carcinogenesis with four different chemical carcinogens.
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PMID:Promotion of liver cancer development by brief exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or carbon tetrachloride. 629 53

The effects of pre- (initiation stage) and post- (promotion stage) administration of 17 chemical carcinogens (including both hepatic and non-hepatic carcinogens), 3 promoters and 2 non-carcinogenic analogs, on the induction of liver hyperplastic nodules were investigated in rats. Test chemicals were administered during the initiation stage after which rats were fed dietary N-2-fluorenylacetamide (2-FAA) for 2 weeks in conjugation with necrogenic CCl4 to enhance production of nodules initiated by test chemicals. Alternatively, effects of test chemicals administered during the promotion phase were evaluated in rats given a combination of dietary 2-FAA for 2 weeks and necrogenic CCl4. This initiation regimen resulted in very few nodules unless a promoter was subsequently used. All chemical carcinogens administered during the initiation stage induced more frequent, larger hyperplastic nodules than did control treatments. However, neither the promoters nor the non-carcinogenic analogs induced hyperplastic nodules if they were administered during the initiation stage. In contrast, hepatocarcinogens and a promoter of hepatocarcinogenesis (phenobarbital) administered in the promotion stage had enhancing (promoting) activity on hyperplastic liver nodules, whereas non-hepatocarcinogens, a promoter for skin carcinogenesis (12-O-tetradecanoylphorbol-13-acetate) and a promoter for urinary bladder carcinogenesis (saccharin) did not. Non-carcinogenic analogs were not active when administered during either the initiation or promotion stages. These findings demonstrated the utility of employing short-term in vivo assays for both initiating and enhancing (promoting) activities of chemicals. By our system, chemicals were classified into 4 main groups, namely, (i) hepatocarcinogens which have both initiating and enhancing activity, (ii) non-hepatocarcinogens with initiating activity only, (iii) promoters of hepatocarcinogenesis which have promoting activity and (iv) non-carcinogens and non liver promoters which did not initiate nor promote nodule development. This is a more discriminating means of assaying carcinogenic activity than is possible with short-term in vitro screening assays for mutagenicity.
Carcinogenesis 1983
PMID:Survey of various chemicals for initiating and promoting activities in a short-term in vivo system based on generation of hyperplastic liver nodules in rats. 630 2

The influence of high doses of retinol acetate (RA) fed with the diet and carbon tetrachloride (CCl4) injected intraperitoneally into rat offspring on transplacental carcinogenic effect of N-nitrosoethylurea (NEU) was studied. Neither RA nor CCl4 affected significantly the development of the nervous system and kidney tumors induced transplacentally by NEU. CCl4 did not induce liver tumors either under these conditions. Obviously, it is rather difficult to modify the transplacental carcinogenesis.
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PMID:[Influence of retinol acetate and carbon tetrachloride on the transplacental carcinogenic effect of N-nitrosoethylurea]. 650 38

We have demonstrated that ammonia is oxidized to nitrate in the rat. Male Sprague-Dawley rats gavaged with 1000 mumol N-15-ammonium chloride each day for 5 days were found to excrete low, but significant amounts of excess N-15-nitrate in their urines on the five days of treatment and on the five subsequent days. We recovered a total of 0.28 +/- 0.03 mumol excess N-15-nitrate (mean +/- SE) per rat, which indicates that ammonia is converted to nitrate in a yield of approximately 0.0080%. The oxidation of N-15-labeled glycine and L-glutamic acid to N-15-nitrate could not be detected. N-15-Hydroxylamine was oxidized in the rat to N-15-nitrate in a yield of 4.7%, which shows that hydroxylamine is a possible intermediate in the ammonia oxidation process. Injection of rats with Arochlor 1254, an inducer of several isozymes of cytochrome P-450, did not significantly affect the rate of endogeneous nitrate synthesis. Carbon tetrachloride, which causes hepatic lipid peroxidation, produced a small but significant increase in nitrate synthesis. We confirmed the observation that a bacterial endotoxin can greatly stimulate nitrate synthesis, and we showed that concurrent treatment with superoxide dismutase does not modify the effect of the endotoxin. An in vitro chemical model system was used to demonstrate that oxidation of ammonia to nitrate by the hydroxyl radical at physiological pH is chemically feasible. Our results are consistent with the hypothesis that ammonia is oxidized to nitrate in vivo by a non-enzymatic process which involves active oxygen species such as the hydroxyl radical. We estimate that a 215 g rat produces 3.0 mumol of nitrate per day via ammonia oxidation.
Carcinogenesis 1984 Jan
PMID:Oxidation of ammonia and hydroxylamine to nitrate in the rat and in vitro. 669 89

The effect of CCl4 pretreatment (dose range from 0.5 to 2.0 ml/kg body weight) on the pathways of dimethylnitrosamine (DMN) metabolism was investigated. The oxidative-N-demethylation by the enzymes, DMN-demethylase I and II operating at low (4 mM) and high (200 mM) substrate concentration, respectively, was greatly reduced in a dose-dependent manner. In addition, the generation of an electrophilic intermediate capable of methylating DNA, specifically at the N-7 and O-6 positions of guanine, was completely inhibited by CCl4 (0.5 ml/kg body weight) pretreatment. When indole feeding (1% in the diet for 8 days prior to CCl4 administration) was employed as a means to enhance DMN-demethylase activities, it was found that the reduction of DMN-demethylase activities was more pronounced in these rats than in the controls. In agreement with earlier findings, 7-methylguanine and O6-methylguanine were not detectable in the CCl4 pretreated group. These results suggest that CCl4 exerts a strong inhibitory action on hepatic DMN metabolism, in particular on the pathway leading to alkylation of DNA guanine. This phenomenon may explain the protective role of CCl4 against DMN-induced hepatotoxicity and perhaps, carcinogenicity, believed to be closely associated with the abnormal modifications of DNA.
Carcinogenesis 1983
PMID:Inhibitory effects of carbon tetrachloride on dimethylnitrosamine metabolism and DNA alkylation. 685 Sep 83

A growing body of evidence from human and animal cancer cytogenetics studies indicates that aneuploidy is an important chromosome change in carcinogenesis. To understand the role of this genetic phenomenon during the first steps of an experimental cancer model, molecular and cellular techniques were combined. A sequential cytogenetic study of a modified Solt-Farber liver cancer model in the rat was performed to identify the importance of chromosome versus genome mutations. Male Wistar rats were initiated with diethylnitrosamine (DENA), followed by a 2-acetylaminofluorene exposure to select resistant hepatocytes. Chronic phenobarbital (PB) treatment was used to induce promotion. Cell proliferation was induced by a necrogenic dose of CCl4, administered during the selection period (Gerlans protocol) or 3 days before hepatocyte isolation (experimental protocol). In order to discriminate between genetic events causing chromosome breakage (clastogenic) and those that induce chromosome loss (aneugenic), isolated micronucleated hepatocytes (MNH) were analysed for the presence of a centromere in the micronucleus (MN). Non-radioactive in situ hybridization with a rat centromere satellite 1 DNA probe was applied. Our results show that the majority of the observed genetic changes, expressed as MN during different preneoplastic stages, were of clastogenic origin. However, the number of induced aneugenic hepatocytes increased markedly during the promotion period of the Gerlans protocol (approximately 7-fold above control) and during PB exposure in the experimental protocol (approximately 4-fold above control). Additionally, these stages were also characterized by an increased level of MN expression (20.3 < % MNH < 32.8), in comparison with the initiation stage after DENA exposure (13.5 < % MNH < 17.1). Although it is not yet clear if these genetic alterations have a causative nature in neoplastic liver transformation, the use of interphase cytogenetics certainly might lead to a better understanding of the genomic changes which occur during experimental hepatocarcinogenesis.
Carcinogenesis 1995 Aug
PMID:Identification of clastogenic and/or aneugenic events during the preneoplastic stages of experimental rat hepatocarcinogenesis by fluorescence in situ hybridization. 763 10

Caloric restriction causes a generalized decrease in growth rate and has been shown to delay the development of both spontaneous and induced neoplasia. In contrast to chronic food restriction, the extreme condition of fasting/refeeding is associated with an overall increase in cell turnover in several organs, including liver, compared with regular feeding. The present study was therefore designed to investigate the effect of complete food withdrawal followed by refeeding on the growth of hepatocyte nodules in initiated rat liver. Male Fischer 344 rats were given a single dose of diethylnitrosamine (DEN, 200 mg/kg i.p.) and then, starting 1 wk later, they were exposed to one or three cycles of fasting (3 days) followed by refeeding (11 days). The control group was fed continuously. Seven weeks after DEN administration all rats were subjected to the resistant hepatocyte model (2-acetylaminofluorene coupled with CCl4) and 2 weeks later 2/3 partial hepatectomy (PH) was performed. All animals were killed 2 weeks after surgery. At PH rats given one cycle of fasting/refeeding had significantly larger glutathione S-transferase 7-7-positive hepatic lesions compared with controls (mean area 0.73 +/- 0.04 versus 0.50 +/- 0.05 mm2, P < 0.025; mean percent area 25.6 +/- 3.2 versus 12.4 +/- 0.9, P < 0.005), while no significant change was observed in their number. The observed differences were more pronounced with three cycles of fasting/refeeding. A similar pattern of results was obtained at the time of killing. It is concluded that fasting/refeeding can exert a positive effect on the growth of rat hepatocyte foci and nodules, in contrast to the general inhibitory effect on carcinogenesis caused by food restriction.
Carcinogenesis 1995 Aug
PMID:The enhancing effect of fasting/refeeding on the growth of nodules selectable by the resistant hepatocyte model in rat liver. 763 16

The interaction between free radicals derived from the catalytic decomposition of bromotrichloromethane and 5-methylcytosine (5MC) under different conditions were studied. The structures of the reaction products formed was established by the GC/MS analysis of their trimethylsilyl derivatives. Under anaerobic conditions, the formation of the following products was found: (1) thymine; (2) 5-hydroxymethyl uracil. Under aerobic conditions, the following reaction products were identified: (1) The same two products formed under anerobic conditions. (2) Monohydroxylated thymine. Precise location of the hydroxyl group was not established but probably corresponds to the six position isomer. (3) Two monochloro monohydroxy thymines. It is suggested that they are cis-trans isomers whose substituents are located at the 5-methyl and six positions of the base. (4) The trimethylsilyl derivative of thymine glycol. (5) Two monobromo monohydroxy adducts of thymine. One of them was detected as its underivatized form in the hydroxyl group position. (6) A partially silylated dihydroxythymine. When benzoyl peroxide was omitted from aerobic incubation mixtures, the compounds formed changed. No longer observable were: thymine; the two monochloro monohydroxy derivatives of thymine; thymine glycol, and one monohydroxythymine. On the other hand, two new reaction products were formed instead: a partially silylated monochloro-monohydroxy thymine and 5-hydroxymethyl-cytosine. If similar or equivalent reaction products were formed in DNA during CBrCl3 or CCl4 poisoning, results might be of relevance, because the 5MC content in DNA from eukaryotes is related to differentiation, gene control, and to carcinogenesis.
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PMID:5-methylcytosine attack by free radicals arising from bromotrichloromethane in a model system: structures of reaction products. 783 48

Liver carcinogenesis is considered to be a good experimental model to study the sequential changes leading to cancer and was applied here for the analysis of chromosome/genome mutations. Since the micronucleus test was shown to be an adequate method to detect and analyse chromosome changes in dividing cells, the frequency of micronuclei (MN) together with their relative DNA content (DNA content of the MN divided by the DNA content of the corresponding nucleus) were analysed in hepatocytes isolated from rats at different stages of experimentally induced hepatocarcinogenesis. The protocol used for the induction of liver cancer was based on the triphasic 'Gerlans protocol', a Solt-Farber procedure supplemented with a phenobarbital (PB) promotion step. Male Wistar rats were initiated by a single i.p. dose of diethylnitrosamine (DENA), followed by selection of the resistant hepatocytes by 2-acetylaminofluorene (2-AAF). Subsequent promotion was accomplished by chronic exposure to phenobarbital. For each group of rats a mitotic stimulator (CCl4) is necessary at the end of their treatment period to express the clastogenic and/or aneugenic lesions which may lead to micronuclei. The results of these experiments do confirm that genetic alterations are occurring at the chromosome level (MN expression) during the different steps of experimental rat liver carcinogenesis. DNA measurements seem to be a good genetic parameter to detect eventual differences between the chromosomal content (whole chromosome or chromosome fragments) of MN populations appearing in different stages of the carcinogenic process. Moreover, a comparison between the mono- and bi-nucleated cell population showed that the frequency of micronuclei is higher in mononuclear parenchymal liver cells.
Carcinogenesis 1993 Nov
PMID:Frequency and DNA content of micronuclei in rat parenchymal liver cells during experimental hepatocarcinogenesis. 824 71


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