Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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.
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PMID:Modulation of cytotoxic and genotoxic effects of 2-acetylaminofluorene in rat and hamster hepatocytes by 3-methylcholanthrene pre-treatment. 374 28

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.
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PMID:Methylation of DNA guanine during the course of induction of liver cancer in hamsters by hydrazine or dimethylnitrosamine. 381 39

Data on potential risk factors for primary liver cancer (PLC), including hepatitis B virus (HBV) infection, contaminated drinking water, maize consumption, and use of tobacco and alcohol were collected from 12,222 males over 40 years of age living on Chongming Island, a high-risk area for PLC. During the first 3 years of follow-up (1980-82), 70 deaths from this disease occurred among study subjects. Preliminary results indicate that HBV carriers were 6.7 times more likely to die of PLC than were noncarriers (P less than .05). No association was found between PLC and alcohol consumption. More data are needed for evaluation of the relationships between cigarette smoking, maize consumption, contaminated drinking water, and PLC on Chongming Island.
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PMID:Hepatitis B virus and primary liver cancer on Chongming Island, People's Republic of China. 383 35

Monolayers of hepatocytes from mouse, hamster, rat, and guinea pig metabolized 2-acetylaminofluorene (AAF) to ether-extractable, water-soluble as well as covalently macromolecular bound products. Hamster hepatocytes showed the highest rate of formation of ether-extractable metabolites, rat and guinea pig the lowest. These species differences reflected mainly differences in the formation of 2-aminofluorene, the dominating ether-extractable metabolite formed. Detectable levels of N-hydroxy-AAF (greater than 1 nmol/10(6) cells) were only obtained with hamster hepatocytes. The major C-hydroxylated metabolites in the species tested were 7- and 9-hydroxy-AAF. Hepatocytes from guinea pig and hamster showed the highest rate of formation of C-hydroxylated and water-soluble metabolites, rat hepatocytes the lowest. The highest rate of covalent macromolecular binding by AAF metabolites was found with hamster hepatocytes, followed by hepatocytes from rat, guinea pig, and mouse. The balance between activation and detoxification reactions of AAF in hepatocytes may be expressed as the ratio between covalently bound metabolites and the sum of C-hydroxylated and stable water-soluble metabolites. This ratio was far greater in rat hepatocytes followed by hamster, guinea pig, and mouse, and it correlated better with the species susceptibility to liver cancer than covalent binding as such. Thus, AAF-induced liver cancer may depend more on the relative degree of activation versus detoxification of the administered dose than on the absolute capacity of the liver to activate the carcinogen.
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PMID:Species differences in the metabolism of 2-acetylaminofluorene by hepatocytes in primary monolayer culture. 394 51

A total of 69 bladder cancer, 76 lung cancer and 59 liver cancer deceased cases and 368 alive community controls group-matched on age and sex were studied to evaluate the association between high-arsenic artesian well water and cancers in the endemic area of blackfoot disease (BFD), a unique peripheral vascular disease related to continuous arsenic exposure. According to a standardized structured questionnaire, information on risk factors was obtained through proxy interview of the cases and personal interview of the controls. A positive dose-response relationship was observed between the exposure to artesian well water and cancers of bladder, lung and liver. The age-sex-adjusted odds ratios of developing bladder, lung and liver cancers for those who had used artesian well water for 40 or more years were 3.90, 3.39, and 2.67, respectively, as compared with those who never used artesian well water. Multiple binary logistic regression analyses showed that the dose-response relationships and odds ratios remained much the same while other risk factors were further adjusted.
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PMID:A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan. 396 42

Enzymatic conversion of tegafur was studied using a thymidine phosphorylase preparation purified from human liver cancer. Tegafur dissolved in water slowly decomposed to 5-FU upon storage at 37 degrees C and this conversion was further activated with an addition of a thymidine phosphorylase preparation. Analysis of Tegafur and 5-FU was performed on a high performance liquid chromatograph. The Km value was in agreement with Michaelis-Menten Kinetics and 2.44 X 10(-2) M without thymidine phosphorylase preparation. When the preparation was added, it was 2.53 X 10(-4) M and 1.75 X 10(-3) M, respectively. Determination of 5-FU concentrations in blood, normal and tumor tissues following a long term administration of Tegafur was performed. The highest concentration of 5-FU was detected in tumor tissue followed by normal tissue and blood, suggesting a human liver thymidine phosphorylase was capable of converting Tegafur to 5-FU more actively in tumor tissue than in normal tissue.
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PMID:[Enzymatic conversion of tegafur in human tumor tissue]. 640 7

Dietary feedback control (DFC) of hepatic cholesterol synthesis is absent or defective in hepatomas of trout, mouse, rat and man. DFC has also been shown to be defective in rats fed several liver carcinogens including 2-acetylaminofluorene (AAF). These studies have led to the hypothesis that loss of normal DFC is an early and consistent event in the development of liver cancer. To determine whether DFC was defective in "precancerous" mouse livers, we fed the liver carcinogens AAF (0.05% in chow) and benzidine (0.02% in drinking water) to male BALB/c and C57BL/6 mice for 3 or 6 weeks. We measured sterol synthesis as incorporation of 2-14C-acetate into digitonin-precipitable sterols by liver slices. DFC was tested by adding 2% cholesterol to the diet for 3 days prior to sacrifice. Benzidine (but not AAF) treatment enhanced sterol synthesis in C57BL/6, but not in BALB/c, mice. However DFC was normal in both strains with either carcinogen. The results indicate that defective DFC is not a consistent early finding in animals fed liver carcinogens. Since defective DFC has been a consistent finding in AAF-fed rats, additional research is needed to determine whether the same genetic factors which determine susceptibility to chemically-induced neoplasia are also important in influencing DFC in carcinogen-fed animals.
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PMID:Feedback control of cholesterol biosynthesis in mice fed the liver carcinogens benzidine and 2-acetylaminofluorene. 709 37

Dietary feedback control (DFC) of hepatic cholesterol synthesis is absent in hepatomas of trout, mouse, rat and man. DFC has also been shown to be defective in rats fed several liver carcinogens, including 2-acetylaminofluorene (AAF). These studies have led to the hypothesis that loss of normal DFC is an early and necessary event in the development of liver cancer. To test this hypothesis, we fed the liver carcinogens benzidine (0.006% in drinking water) or AAF (0.05% in chow) to male Sprague-Dawley rats for either 3 or 6 weeks. We measured cholesterol synthesis as the incorporation of 2-14C-acetate into digitonin-precipitable sterols by liver slices. DFC was tested by adding 2% cholesterol to the diet for 3 days prior to sacrifice. DFC was defective in the AAF-fed rats but was normal in the benzidine-treated rats. These results are at variance with the previously stated hypothesis and, for the first time, suggest that defective DFC is not a consistent finding in the early stages of liver carcinogenesis. Additional research is necessary to explain why DFC is altered by exposure to some liver carcinogens such as AAF but unaffected by exposure to others such as benzidine.
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PMID:Feedback control of cholesterol biosynthesis in rats fed the liver carcinogens benzidine and 2-acetylaminofluorene. 724 21

The effects of treatment in a hydrated autoclave (121 degrees C, 2 atm for 20 min), microwave oven (in water), and simple heating (60 degrees C overnight in distilled water or 90 degrees C for 10 min in ZnSO4) on the stainability of 56 antigens by commercially available antibodies in formalin-fixed paraffin-embedded tissue sections were evaluated. The detectability of nuclear antigens, glycoprotein, lymphocytic surface markers, and chromogranin A was significantly and reproducibly improved by these treatments, whereas the detectability of viral antigens and peptide hormones was attenuated or unchanged. This enhancement includes not only the distinctiveness of the positive staining, but also the number of positive cells, as revealed by comparing serial sections. Among these four heating procedures, microwave heating and autoclaving were more effective than the others on p53, c-erbB-2, and CA125, whereas simple heating was best for smooth-muscle actin (HHF35 and CGA7). Generally the effects of the heating procedures for these antigens were consistent among the cases, but the effects on GFAP varied with the case. The alterations we observed could significantly influence the interpretation of immunohistochemical staining of currently popular tumor markers such as p53 in terms of their prevalence (28% vs 64% in gastric cancer; 36% vs 82% in metastatic liver cancer) and other diagnostically important markers.
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PMID:Alteration of immunoreactivity by hydrated autoclaving, microwave treatment, and simple heating of paraffin-embedded tissue sections. 751 73


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