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

The present work has been planned in order to elucidate the effect of phenobarbital (PB: 15 mg per rat of ingested dose) on carcinogenesis when it is administered simultaneously with diethylnitrosamine (DEN: 10 mg/kg/day). Wistar rats (180 g) were treated by DEN alone or by DEN + PB during 2, 4 and 6 weeks according to our schedule for hepatocarcinogenesis. After the end of the treatment, the number and the size of induced PAS positive preneoplastic foci was significantly reduced when PB was given simultaneously with DEN for 4 and 6 weeks. The mitotic inhibition and the production of micronuclei normally observed after partial hepatectomy in DEN treated rats were also significantly decreased in DEN + PB treated rats. When the treatment last only 2 weeks, the presence of PB did not change significantly the last parameters. In DEN + PB treated rats, the survival was prolonged and the tumor incidence decreased as compared with the results obtained by DEN alone. It is concluded that PB, which promotes carcinogenesis when administered after the DEN treatment, reduces the carcinogen effect when given simultaneously with DEN. This 'anti-carcinogen' effect acts on the initiation as well as on the promotion of the precancerous lesions. Biochemical investigations are in progress to obtain more information about this 'paradoxical' PB effect.
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PMID:Anti-carcinogenic action of phenobarbital given simultaneously with diethylnitrosamine in the rat. 378 Aug 14

Acetaminophen (ACT), the most commonly used analgesic and antipyretic in the United States, was previously demonstrated to be a hepatocarcinogen in one mouse study but not in rats. In order to help elucidate the potential mechanisms of carcinogenesis by this nongenotoxic chemical and its relationship to hepatotoxicity, ACT was fed to groups of 60-120 male B6C3F1 mice at dietary concentrations of 5000 or 10,000 ppm from 6 weeks of age for periods of up to 70 weeks to study the hepatotoxic effects of ACT. To test for potential liver tumor-promoting effects of ACT, N-nitrosodiethylamine (DEN) was injected intraperitoneally at 40 mg/kg into additional groups of 30-60 male B6C3F1 mice at 4 weeks of age. Two weeks later some mice received ACT at dietary concentrations of 5000 or 10,000 ppm. Mice were sacrificed either at 24 weeks after DEN injection or after 22 or 70 weeks of ACT exposure. The livers were weighed and prepared for qualitative and quantitative histological evaluation of focal hepatocellular proliferative lesions (FHPL) including microscopic hyperplastic foci and neoplasms by automated image analysis. At 24 weeks the incidence and number of FHPL per square centimeter were significantly increased only in DEN-treated mice receiving 10,000 ppm ACT. Chronic hepatotoxicity was mild at this time. At 72 weeks ACT alone had no effect on the incidence or number of naturally occurring liver tumors despite severe chronic hepatotoxicity and suppression of body weight gain in mice receiving 10,000 ppm and only mild toxicity at 5000 ppm. There were histological findings suggesting that the chronic hepatotoxicity had, in part, a vascular pathogenesis. This study provided evidence against the hypothesis that chronic hepatotoxicity, in and of itself, results in an increased incidence of naturally occurring liver tumors in mice.
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PMID:The chronic hepatotoxic, tumor-promoting, and carcinogenic effects of acetaminophen in male B6C3F1 mice. 378 Nov 28

Selected inbred strains of mice were compared with respect to their susceptibility to two-stage liver carcinogenesis. Five-week-old male mice of strains C57BL/6NCr (C57), C3H/HeNCrMTV- (C3H) and DBA/2NCr (DBA) were given a single i.p. injection of N-nitrosodiethylamine (DEN, 90 mg/kg body weight) or the solvent tricaprylin (10 ml/kg). Beginning 2 weeks later, half of the DEN-treated and half of the control mice were given drinking water containing 0.05% phenobarbital (PB). Ten mice from each treatment group were killed at 12, 24, 36 and 52 weeks of age (5, 17, 29 and 45 weeks exposure to PB). PB significantly increased both the number of hepatocellular foci/cm2 and the incidence of hepatocellular tumors after 17 weeks of treatment in 24-week-old DEN-initiated mice of strains C3H (0.11 +/- 0.07 versus 2.9 +/- 0.3 foci/cm2 and 20 versus 70% incidence of hepatocellular tumors) and DBA (0.09 +/- 0.09 versus 3.72 +/- 0.6 foci/cm2 and 0 versus 90% incidence of hepatocellular tumors) but was ineffective in C57 mice (0.04 +/- 0.04 versus 0.07 +/- 0.07 foci/cm2). At 36 weeks of age the incidence of liver cell tumors in mice given DEN but not PB was 10 (DBA), 10 (C57) and 50% (C3H); the incidence was increased by PB to 90% in DBA and 100% in C3H mice, but there was no increase in C57 mice. Even at 52 weeks, the low incidence of hepatocellular tumors in C57 mice given DEN only (20%) was not significantly increased by subsequent exposure to PB. Serum PB levels observed at 12, 24 and 36 weeks of age were significantly higher in DBA mice than in C57 or C3H mice. Similar results were observed in a separate study in which PB was administered in drinking water to 7-week-old male mice of these three strains for 20 days, during which period serum PB levels were measured at shorter intervals. DBA mice thus appear to be unable to metabolize PB, which itself rather than its metabolites is probably responsible for tumor-promoting effects. DBA mice were especially sensitive, while C57 mice were refractory to promotion of hepatocarcinogenesis by PB. These two strains, which differ with respect to other significant parameters for chemical carcinogenesis including inducibility for aryl hydrocarbon hydroxylase and susceptibility to promotion of hydrocarbon-initiated skin tumors by 12-O-tetradecanoylphorbol-13-acetate, thus also provide a means for analysis of the pharmacogenetics of susceptibility to hepatocellular tumor promotion.
Carcinogenesis 1986 Feb
PMID:Interstrain differences in susceptibility to liver carcinogenesis initiated by N-nitrosodiethylamine and its promotion by phenobarbital in C57BL/6NCr, C3H/HeNCrMTV- and DBA/2NCr mice. 394 11

Recent experiments have demonstrated that O6-alkylguanine is rapidly removed from hepatocyte DNA following continuous exposure to 1,2-dimethylhydrazine or diethylnitrosamine. In contrast, O4-ethyldeoxythymidine accumulates to concentrations more than 50 times greater than O6-ethyldexyguanosine. Studies on the formation and persistence of O4-methyldeoxythymidine in vivo have not been reported. This study reports the development of sensitive radioimmune assays to O4-methyldeoxythymidine and O4-ethyldeoxythymidine. Utilizing this method, the accumulation and removal of O4-methyldeoxythymidine and O4-ethyldeoxythymidine in liver DNA from rats exposed to 1,2-dimethylhydrazine or diethylnitrosamine were measured. The results demonstrated that O4-methyldeoxythymidine was formed at an O6-methylguanine/O4-methyldeoxythymidine ratio of approximately 100/1 and was repaired with a half-time of approximately 20 h. In contrast, O4-ethyldeoxythymidine removal was 13 times slower with a t 1/2 of approximately 11 days after both pulse dose and cessation of continuous DEN administration. Combined with previously reported data, results presented here suggest that (i) despite a lower rate of formation, O4-methyldeoxythymidine becomes nearly equal in importance to O6-methylguanine as a promutagenic adduct in hepatocytes from continuously exposed rats and (ii) differential repair of O4-alkylthymidine adducts provides a mechanism that may explain in part the superior ability of ethylating versus methylating agents to induce hepatocellular carcinomas in the rat.
Carcinogenesis 1985 Apr
PMID:Differential repair of O4-alkylthymidine following exposure to methylating and ethylating hepatocarcinogens. 398 64

Using a newborn rat model for carcinogenesis, changes in liver cytosolic proteins at three stages of tumorigenesis, on Days 21, 97, and 120, by mirex (dodecachloropentacyclo-1,3,4-metheno-2H-cyclobuta[cd] pentalene), and diethyl- and dimethylnitrosamines (DEN and DMN) were studied. Following multiple exposure to the hepatocarcinogens, groups of weanling rats were given dietary phenobarbital (PB) up to 120 days. SDS-PAGE separation of cytosolic proteins showed that at 21 days, prior to PB, two proteins of 26K and 23K mol wt were significantly induced by mirex and DMN while a high mol wt 63K protein was induced only by DEN and DMN. During the period of PB treatment up to 97 days, these proteins were well sustained at a higher level. A marked increase in 21K protein band was also observed at this point. In tumor tissues obtained from DEN and DMN rats continued on PB diet for 120 days, the high level of 63K protein was seen only in DEN and not in DMN tumor. The tumors also showed a significant reduction in 25K protein compared to 21- and 97-day groups. The presence of even lower mol wt proteins of 14-21K was seen in tumors. The early detection and further characterization of these low mol wt proteins may provide clues as to whether they are preneoplastic markers or oncogene products as speculated by other investigators. Moreover, certain similarities in the induction of cytosolic proteins by "epigenetic" and "genotoxic" carcinogens raise more interesting questions regarding the mechanisms of action of these distinct classes of carcinogens.
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PMID:Comparative changes in rat liver cytosolic proteins by mirex, diethylnitrosamine, and dimethylnitrosamine exposure. 404 62

1. The incorporation of methyl groups into histones from dimethylnitrosamine and from methionine was studied by injection of the labelled compounds, isolation of rat liver and kidney histones, and analysis of hydrolysates by column chromatography. 2. Labelled methionine gave rise to labelled in-N-methyl-lysine, di-in-N-methyl-lysine and an amino acid presumed to be omega-N-methyl-arginine. 3. Administration of labelled dimethylnitrosamine gave rise to labelled S-methylcysteine, 1-methylhistidine, 3-methylhistidine and in-N-methyl-lysine derived from the alkylating metabolite of dimethylnitrosamine. In addition, labelled formaldehyde released by metabolism of dimethylnitrosamine leads to the formation of labelled S-adenosylmethionine, and hence to labelling of in-N-methyl-lysine, di-in-N-methyl-lysine and omega-N-methylarginine by enzymic methylation. 4. The formation of in-N-methyl-lysine by alkylation of liver histones was confirmed by using doubly labelled dimethylnitrosamine to discriminate between direct chemical alkylation and enzymic methylation via S-adenosylmethionine. These experiments also suggested the possibility that methionine residues in the histones were alkylated to give methylmethionine sulphonium residues. 5. The extent of alkylation of liver histones was maximal at about 5h after dosing and declined between 5 and 24h. The methylated amino acids resulting from direct chemical alkylation were preferentially lost: this is ascribed to necrosis of the more highly alkylated cells. 6. Liver histones were about four times as alkylated as kidney histones; the extent of alkylation of liver histones was similar to that of liver total nuclear proteins. 7. Methyl methanesulphonate (120mg/kg) alkylated liver histones to a greater extent than did dimethylnitrosamine. Diethylnitrosamine also alkylated liver histones. 8. The results are discussed with regard to the possible effects of alkylation on histone function, and the possible role of histone alkylation in carcinogenesis by the three compounds.
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PMID:Methylation of nuclear proteins by dimethylnitrosamine and by methionine in the rat in vivo. 513 29

The tumor initiating activities of nitrosomethylbenzylamine (NMBzA), an esophageal carcinogen, and nitrosodimethylamine (NDMA), a hepatocarcinogen, were compared in rat liver using modifications of the initiation assays of Tsuda et al. (Cancer Res., 40, 1157, 1980) and Pitot et al. (Nature, 271, 456, 1978). Equimolar doses of NMBzA or NDMA (33.5 mu-mol/kg) were injected i.p. into male Sprague-Dawley rats 18 h after partial hepatectomy. Following selection, foci of preneoplastic hepatocytes were detected by histochemical staining for gamma-glutamyltranspeptidase. Nitrosomethylamylamine (NMAmA), 115 mumol/kg), also an esophageal carcinogen, was tested in the assay of Tsuda et al., and nitrosodiethylamine (NDEA, 33.5 mumol/kg), a hepatic and esophageal carcinogen, was tested in the assay of Pitot et al. Both NDMA and NDEA induced significant increases in the number of preneoplastic foci above background. In contrast, neither NMBzA nor NMAmA increased the number of foci above background. Microsomes from regenerating liver had a lower capacity to metabolize both NDMA and NMBzA compared to microsomes from intact liver, but the decrease in activity was similar for both compounds. Neither NDMA nor NMBzA significantly inhibited the first wave of DNA synthesis in vivo in the regenerating liver. The results demonstrate that in contrast to NDMA and NDEA, NMBzA and NMAmA lack tumor initiating activity in the liver.
Carcinogenesis 1982
PMID:Comparative tumor initiating activities of N-nitrosomethylbenzylamine and N-nitrosodimethylamine in rat liver. 612 25

With the view of studying the role of autonomic nervous system in chemical carcinogenesis mechanism in outbred white male rats, chronically treated with NDEA, there has been investigated the modifying effect of some neurotropic pharmacological drugs which cause either stimulation or inhibition of: 1. adrenergic processes (noradrenalin, isoproterenol, clonidine, pyrroxane and propranolol); 2. cholinergic processes (proserine and atropine); 3. the function of the central nervous system (CNS)--caffeine and ethanol. Pharmacological activation of alpha-adrenoreceptors or blocking of both beta-adrenoreceptors and cholinoreceptors has been revealed to stimulate hepatocarcinogenesis. On the contrary, the administration of alpha-adrenoreceptors antagonist or beta-adrenoreceptor and cholinoreceptors agonists inhibited the process of carcinogenic transformation. Caffeine, being the CNS stimulator, has significantly promoted carcinogenesis, while ethanol has practically prevented NDEA effect. Clonidine has also demonstrated its anticarcinogenic action. The obtained data are being discussed in connection with chemical carcinogenesis influence upon the CNS integrative function in control and regulation of tissue homeostasis.
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PMID:On participation of the autonomic nervous system in the mechanisms of chemical carcinogenesis. 612 35

The ability of N-nitrosodiethylamine (DENA) to induce transformation of the mammary cells was studied in culture of the whole mammary organ from BALB/c female mice. Incidence of nodule-like alveolar lesions (NLAL) in the glands in vitro has been as a measure of transformation. NLALs are analogous to the precancerous hyperplastic alveolar nodules (HAN) of mouse mammary gland in vivo. The mammary glands were treated with graded concentrations (0.1-2.5 microgram/ml) of DENA during lobuloalveolar morphogenesis in medium (Waymouth's MB752/1) containing insulin, prolactin, hydrocortisone and aldosterone. DENA treatment caused a dose-related increased occurrence of NLAL in the glands in vitro and concentration of 1.5 microgram/ml produced the highest incidence of 85%. The high incidence of NLAL was accompanied by a 3-fold increase of DNA repair activity in the DENA treated glands. Incubation of the glands for 6 days after DENA treatment in medium containing N-4-hydroxyphenyl)retinamide and the same hormone mixture caused 61% inhibition of NLAL incidence. The results indicate that DENA is capable of inducing a high level of transformation of the mammary epithelial cells in vitro and that this retinoid can inhibit expression of the transformed cells acting at the promotional level.
Carcinogenesis 1982
PMID:N-Nitrosodiethylamine-induced nodule-like alveolar lesion and its prevention by a retinoid in BALB/c mouse mammary glands in the whole organ in culture. 621 28

Unscheduled DNA synthesis (UDS) was measured simultaneously in rat hepatocytes and human fibroblasts when combined cultures of the 2 cell types were exposed to procarcinogens. Human fibroblasts were preincubated with 5-bromo-2'-deoxyuridine (BRdU) to substitute for thymidine in the DNA. Hepatocyte DNA was separated from the heavier BRdU-substituted fibroblast DNA by isopycnic centrifugations in neutral cesium chloride and the specific activities of the DNA's were determined. In the presence of hepatocytes, benzo - [a]pyrene (BP) induced more UDS in the fibroblasts than in the hepatocytes. BP induced no UDS in the fibroblasts in the absence of hepatocytes. Diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) stimulated a significant amount of UDS only in the hepatocytes. Thus, the co-cultures of hepatocytes and fibroblasts responded with UDS to these chemical carcinogens in a manner that parallels the tissue specificity of the carcinogenicity of these chemicals in vivo. That is, the known hepatocarcinogens DEN and AAF, only stimulated significant UDS in the hepatocytes, whereas the non-hepatocarcinogen, BP, though activated in these cultures mainly by the hepatocytes, stimulated more UDS in the fibroblasts than in the hepatocytes. The amount of [3H]BP bound to DNA was investigated in the co-cultures and in cultures of fibroblasts alone. When co-cultures were exposed to [3H]BP the fibroblast DNA had approximately 3 times more BP bound to it (per microgram DNA) than did the hepatocyte DNA. The amount of [3H]BP bound to the DNA of cultures of fibroblasts alone was 29% of the amount bound to the DNA of the fibroblasts from the co-cultures. Thus, although the hepatocytes were mainly responsible for the activation of BP, more [3H]BP was bound to the fibroblast DNA. It is suggested that the intercellular distribution of carcinogenic metabolites may be a significant determinant of the carcinogenic effect.
Carcinogenesis 1981
PMID:Comparisons of the effects of chemical carcinogens in mixed cultures of rat hepatocytes and human fibroblasts. 626 72


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