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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of ethionine, the ethyl analogue of methionine, as a metabolic probe to study the possible roles of methionine and choline in liver carcinogenesis has been briefly reviewed. Ethionine-induced liver carcinogenesis is similar in many aspects, including initiation, promotion, and progression, to carcinogenesis with other agents. However, the special role of methionine in preventing virtually all metabolic and pathologic effects of ethionine, including liver cancer, places ethionine in a special position. On the basis of these observations and our current knowledge about choline deficiency in the genesis of liver cancer, we proposed that choline and methionine play separate but overlapping roles in the initiation and promotion of liver carcinogenesis.
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PMID:Ethionine in the analysis of the possible separate roles of methionine and choline deficiencies in carcinogenesis. 359 23

The study was designed to assess the syncarcinogenic activity of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDElA) in the liver of 1800 male Sprague-Dawley rats. The N-nitrosamines were administered throughout the rats' lives individually and in combination at three logarithmically spaced dose levels contained in drinking water. The dose levels in the individual dose-response experiments ranged from the lowest concentrations of previous experiments (NDEA, 0.1 mg/kg; NPYR, 0.4 mg/kg; NDElA, 2.0 mg/kg) to dosages 10 times lower and comprised a high, medium and low dose (escalation factor: 3.16). The high dose of the combination contained the three nitrosamine concentrations used as the medium doses of the individual nitrosamines. The medium combination dose resulted from the combined administration of the three lowest dosages, and the low combination dose consisted of three nitrosamine dosages which amounted to one-third of the low dosages respectively. Administration of these dosages was associated with a dose-dependent incidence of liver cancer: NDEA induced 45, 3.8 and 2.5%; NPYR caused 21.3, 5 and 1.3%; NDElA generated 7.5, 1.3 and 2.5%; and the combinations induced 16, 4.2 and 1.7% respectively. Untreated controls showed 0.6% liver cancer incidence. Besides the liver, the gastrointestinal tract, the neurogenic tissue, the urinary tract and the hematopoietic and lymphatic tissue were affected by tumor incidences increased over that of controls. There was, however, no well-defined dose dependency as with the liver tumors. These results indicate dose dependency of liver tumor formation even at very low exposure levels of the individual agents. The carcinogenic effects of the hepatotropic N-nitrosamines summed up in combination. The observed additivity was linear. Dose levels, which alone would presumably not have been carcinogenic, effected a significant cancer risk in combination.
Carcinogenesis 1987 Nov
PMID:Combination experiments with very low doses of three genotoxic N-nitrosamines with similar organotropic carcinogenicity in rats. 366 55

It is well known that 2-acetylaminofluorene (AAF)-induced liver cancer is reduced by simultaneous administration of 3-methylcholanthrene (MC) in the rat, but not in the hamster. The present report examines the effects of MC pre-treatment on the metabolism and toxicity of AAF in monolayer cultures of hepatocytes. Hepatocytes isolated from pre-treated animals of both species metabolized AAF and 2-aminofluorene (AF) to metabolites mutagenic to Salmonella typhimurium more efficiently than hepatocytes from control animals. MC-pre-treated rat hepatocytes showed increased responses to AAF- and AF-induced unscheduled DNA synthesis, while MC-pre-treated hamster hepatocytes were less responsive than the untreated hepatocytes. Increased cytotoxic effects of AAF were observed in MC-pre-treated rat hepatocytes, whereas AAF was not cytotoxic in hamster hepatocytes from either pre-treated or control animals. MC pre-treatment caused increased rates of formation of C-hydroxylated, N-hydroxylated, water-soluble and covalently macromolecular bound AAF metabolites in both species. No significant effect of MC pre-treatment was seen on the formation of AF from AAF. A large decrease in the ratio between covalently macromolecular bound (activated) metabolites and the sum of C-hydroxylated and water-soluble (detoxified) AAF metabolites, was seen after MC pre-treatment of rat hepatocytes, whereas no or only a minor decrease was observed in hamster hepatocytes. This ratio correlated much better with the in vivo carcinogenicity data than the other parameters such as mutagenicity, DNA repair or covalent macromolecular binding. Thus, the hypothesis that AAF-induced liver cancer depends less on the rate at which AAF is activated, but more on the relative proportion of the dose which is activated, is supported by the present data.
Carcinogenesis 1986 Sep
PMID:Modulation of cytotoxic and genotoxic effects of 2-acetylaminofluorene in rat and hamster hepatocytes by 3-methylcholanthrene pre-treatment. 374 28

In order to check whether the benzodiazepine, oxazepam (OZ), has a modulating effect on the development of liver cancer, it was given to rats previously submitted to two different protocols of hepatocarcinogenesis: the resistant hepatocyte protocol and Pitot's model (initiation-promotion). Its effects were compared with those of phenobarbital (PB) administered under the same conditions. As compared with basal diet, a diet containing 0.05% of PB and 0.1% of OZ enhanced, in both models, the development of gamma-glutamyltransferase-positive lesions in early stages. OZ also had a promoting effect on the development of liver cancers in later stages in both models whereas PB only enhanced it in the resistant hepatocyte protocol. Thus, like PB, OZ may have a promoting effect on liver cancer in rats.
Carcinogenesis 1987 Jan
PMID:Promoting effect of oxazepam in rat hepatocarcinogenesis. 380 99

Hydrazine is carcinogenic to the mouse and rat, but three earlier studies have reported no carcinogenicity of hydrazine in the hamster. Administration of hydrazine to mice, rats and hamsters results in rapid methylation of liver DNA guanine for which endogenous formaldehyde appears to be the source of the methyl moiety. Hamsters were given hydrazine sulfate at 170, 340 and 510 mg/l in the drinking water for 2 years [average dose of 4.6, 8.3 and 10.3 mg hydrazine (free base)/kg body wt over the 2-year period], during which levels of methylation of DNA guanine in liver, kidney and lung, and histopathologic examinations of these tissues were carried out; dimethylnitrosamine, as a positive control, was administered at 10 mg/l in the drinking water (average dose of 1.1 mg/kg body wt over the 4-month measurement period). Both 7-methylguanine and O6-methylguanine were readily detectable at 6 months exposure in hamsters given hydrazine or dimethylnitrosamine; in hydrazine-treated animals only trace amounts of these bases could be detected after 12 months exposure; these bases were again detected in liver DNA at exposure times of 18 and 24 months. Hepatocellular carcinomas were observed in hamsters treated at the highest dose of hydrazine sulfate after 78 weeks of exposure; the incidence of liver cancer was dose-related over the course of the experiment: 32% for hamsters exposed to 510 mg hydrazine sulfate/l, 12% for 340 mg/l and none at 170 mg/l. Hamsters given dimethylnitrosamine developed high levels of 7-methylguanine and even higher levels of O6-methylguanine and both liver cholangiocellular carcinomas (73% incidence), as reported before, and hepatocellular carcinomas (27% incidence), a new finding. These results demonstrate for the first time that hydrazine is a liver carcinogen in the hamster and provide new information regarding the accumulation of DNA damage during the entire induction period for the carcinomas.
Carcinogenesis 1987 Mar
PMID:Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. 381 39

Nonhistone chromosomal proteins (NHCP) from normal, regenerating rat liver, fetal liver, stages during acetylaminofluorene (AAF) and diethylnitrosamine (DEN) induced carcinogenesis, and resultant primary hepatocellular carcinomas (PHC) were analyzed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). These studies sought to determine if changes in proteins putatively involved in catalyzing specific gene expression (NHCP) occur during liver cancer development that might be related to the malignant phenotype. NHCP extracted in high salt-urea buffers, analyzed by 2D-PAGE and silver staining were resolved into some 530-560 polypeptides. Increases in number of NHCP amounting to 8.4, 8.6 and 8.8%, respectively, were detected in AAF induced nodules (AAF-NOD), AAF-PHCs and DEN-PHCs when compared to normal chromatins. The majority of the 51 qualitative changes detected reflected cell cycling and/or reexpression of fetal-NHCP. Within the total changes, seven new NHCP were found only in AAF- and DEN-induced PHCs. Further, four NHCP with isoelectric points and relative molecular weights (pI/MW) of 5.62/19.3, 5.96/30.7, 6.25/46.6 and 8.16/53.5 occurring in both AAF- and DEN-PHC also were found in AAF-NOD, a carcinogenesis stage considered to represent premalignant nodules. Reciprocally, three NHCP of pI/mol.wt.: 6.81/34.0, 5.82/43.7 and 8.18/67.0 present in normal liver, disappeared in all carcinogen involved tissues analyzed. These findings indicate that while AAF and DEN exposure results in a number of qualitative NHCP changes specific for the particular carcinogen, a total of only ten changes, seven inductions and three losses, occurred in common during hepatocarcinogenesis induced by these diverse agents. At least four of these NHCP may prove critical inductions during malignant conversion or alternatively might serve as tumor markers since they appear first in a well characterized premalignant stage and persist in resultant tumors.
Carcinogenesis 1985 Mar
PMID:Alterations in nonhistone chromatin proteins during hepatocarcinogenesis induced by diverse acting carcinogens. 397 52

Attention has been drawn in recent years to the diagnostic interest offered by increases in serum gamma GT in the detection of liver metastases and various cancers in man. Although this analysis is not specific and presents a few false positive and negative results, it seems however profitable to include it either in detection or in supervision tests. Furthermore, in the rat and mouse, this enzyme practically absent from the adult liver, reappears during liver cancer Whatever the cause: this onco-foetal character may be useful to exploit in studies of experimental carcinogenesis, but does not seem to be a valid model for the increases observed in man.
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PMID:[Gamma glutamyl transferase and cancer (author's transl)]. 611 90

The sequential treatment of young Wistar rats with two different carcinogens (diethylnitrosamine - plus partial hepatectomy - as an initiator, and 2-acetylaminofluorene as a cytotoxic selection pressure) induces the appearance of foci and nodules of liver cells which are phenotypically altered. By means of an algorithm which takes into account binuclearity as well as cell-to-cell aggregation it is possible to compute cellular ploidy distributions from flow-cytometric analysis of either hepatocyte suspensions or suspensions of hepatocytic nuclei. Cell suspensions isolated from carcinogen-treated rats can be shown to contain, already after 8 weeks, approximately 70% small, diploid hepatocytes, whereas suspensions from normal or partially hepatectomized control livers contain only approximately 10% diploid cells (the remainder being mostly tetraploid). Isolated nodules, i.e., expanding clones of proliferating cells, believed to be neoplastic precursor lesions, contained almost only diploid cells. These observations suggest that the selective outgrowth of a population of small, diploid hepatocytes may be a significant early step in the development of liver cancer.
Carcinogenesis 1984 Oct
PMID:Emergence of a population of small, diploid hepatocytes during hepatocarcinogenesis. 614 24

Conflicting results have been reported on the influence of portacaval anastomosis on liver carcinogenesis. The purpose of this investigation was to study the effect of portal diversion on liver carcinogenesis induced in the rat by a potent chemical liver carcinogen, Aflatoxin B1 (AFB1). Liver tumors appeared earlier and were significantly bigger in rats with shunts than in sham-operated controls. Portal diversion also induced in rats fed AFB1 a splenic atrophy with nearly complete disappearance of Malpighian corpuscles suggesting a profound immunodepression. This might be responsible for the enhancement of liver cancer by portacaval anastomosis in the rats fed AFB1. Thus, the influence of portal diversion on liver cancers appears to be multifactorial.
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PMID:Enhancement of Aflatoxin B1 induced liver carcinogenesis by portal diversion in the rat. 617 61

The sequence of possible cellular, tissue, biochemical, and molecular changes that are important during the development of experimental liver cancer with chemicals is reviewed from the viewpoint of the author's experience in carcinogenesis over the past 25 years. The development of a new model for the analysis of liver carcinogenesis, the resistant hepatocyte model, is briefly described, as are the known steps between exposure to an initiating dose of a chemical carcinogen to the appearance of hepatocellular carcinoma. These steps include: (a) the interactions with DNA; (b) the dependence on a round of cell proliferation for initiation; (c) one type of initiated hepatocyte, a resistant hepatocyte; (d) the selection of these new hepatocytes, probably by clonal expansion, to form synchronously the first type of hepatocyte nodules, early nodules; (e) the election of the majority of these nodules to undergo remodeling to normal-appearing liver by differentiation ("redifferentiation"); (f) the election of a minority of early nodules to persist; (g) the slow growth of the few persistent nodules; and (h) the precursor role of persistent nodules in the development of hepatocellular carcinoma. The evidence for such a precursor role includes: (a) the common occurrence in persistent nodules of a subsequent precancerous step, "nodules in nodules"; (b) the occurrence of metastasizing cancer inside nodules without cancer elsewhere in the liver; and (c) the high rate of evolution to cancer of persistent nodules, but not of early nodules, when transplanted to the spleen. Based on the common architecture, organization, blood supply, and biochemical pattern of properties relating to the metabolism of xenobiotics in hepatocyte nodules in six different models of liver carcinogenesis and on the common occurrence of a highly programmed redifferentiation pattern of carcinogen-induced hepatocyte nodules, it is concluded that heterogeneity and diversity seen in many phenotypic properties of cancers, including liver cancers, is preceded by a precursor population that is unusually homogeneous and uniform in phenotype. Thus, the heterogeneity and diversity of cancers are probably late manifestations in carcinogenesis. The available evidence is very suggestive that the hepatocyte nodules are an expression of physiological adaptation to exposure to hazardous xenobiotics and not a form of aberration or mutation. The data also suggest that hepatocyte nodules are an additional pattern of liver differentiation and that liver cancer, to be understood, should be compared with this precursor new state rather than the conventional adult, fetal, or embryonic states.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cellular biochemistry of the stepwise development of cancer with chemicals: G. H. A. Clowes memorial lecture. 638 26


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