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

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was evaluated quantitatively in groups of male Sprague-Dawley rats continuously exposed to 0, 6, 12 and 24 mg/kg body wt of N-nitrosomorpholine (NNM) and studied at different time points up to 80, 50, 37 and 20 weeks respectively. Continuous oral administration of NNM resulted in a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA) and carcinomas (HCC) at all dose levels studied. In contrast to earlier stop experiments with 24 mg NNM/kg body wt, there was no reversion-linked phenotypic instability but a rapid progression of FAH of the mixed cell type to a high incidence of hepatocyte nodules and HCC after continuous treatment with NNM at this dose level. At the two lower dose levels of NNM (12 and 6 mg/kg) the well-known sequence of cellular changes leading from glycogenotic (clear, combined clear/acidophilic and acidophilic) to mixed and diffusely basophilic cell populations, in which HCC prevailed. A considerable part of the glycogenotic foci contained exclusively acidophilic cells, and HCA consisting of a mixture of acidophilic and basophilic cells were the most common benign tumour type in these groups. At the end of the observation period there was also a high incidence (> 50%) of HCC at both dose levels, indicating the potential of persistent nodules (HCA) containing acidophilic cells to progress to HCC. FAH and HCA exhibiting a tigroid cell pattern appeared only at the two lower dose levels, but for this type of HCA it remained open whether it may progress to HCC. From a comparison of the different dosing regimens of NNM studied in this and previous experiments we conclude that the rapid, potentially reversible shift from glycogenotic to mixed cell populations at the highest dose level of continuously applied NNM (24 mg/kg) and the high proportion of pure acidophilic glycogen storage foci observed after continuous administration of NNM at the two lower dose levels (6 and 12 mg/kg) represent different phenotypic expressions of promoting effects exerted by the ongoing influence of the carcinogen on FAH initiated by the same compound. The metabolic and molecular changes underlying these 'initiating' and 'promoting' effects of NNM seem to differ in terms of quantity rather than quality.
Carcinogenesis 1994 Jun
PMID:Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced by continuous oral exposure to N-nitrosomorpholine. 802 Jan 61

By a modified serum 64-DP isolation method we successfully isolated alpha-DNA binding protein (alpha DBP) to electrophoretic purity. Analysis by SDS-PAGE revealed a molecular weight of 59,000. It suggested that alpha DBP is a glycoprotein. Goat anti-alpha DBP anti-serum was prepared and single radial immunodiffusion assay was used to screen 256 healthy individuals (teachers, students, workers and peasants) and serum samples from 969 patients with various kinds of cancers. Contrary to previous findings, we found that serum alpha DBP was abundant in healthy individuals with homogeneous precipitation rings, and was not significantly increased in the serum of cancer patients. However, it depicted a heterogeneous pattern with 1-4 rings of various thickness. This phenomenon was observed in 94.2% of patients with liver cancer regardless of the presence or absence of AFP. We would suggest that the change of alpha DBP band from homogeneity to heterogeneity may be a sign of carcinogenesis in the body.
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PMID:[Different manifestation of DNA binding protein in healthy individuals and cancer patients]. 803 42

A proposed mechanism for the metabolic activation of tamoxifen to electrophilic species that form DNA adducts leading to liver cancer involves alpha-hydroxylation of the ethyl group in the critical first step. This mechanism predicts that tamoxifen deuterated at the alpha-position would be less genotoxic than the non-deuterated compound owing to an isotope effect that would reduce the rate of oxidative metabolism at this position. This hypothesis has now been tested with experiments conducted in rats in vivo and in human cells in vitro. It was found that the deuterated compound [D5-ethyl]-tamoxifen is significantly less genotoxic than tamoxifen. Administration of 0.06 and 0.12 mmol/kg [D5-ethyl]-tamoxifen to female Fischer rats by gavage resulted in a 2.5- and 1.7-fold reduction respectively in the levels of hepatic DNA adducts present 24 h after treatment, compared with the non-deuterated compound. Treatment of MCL-5 cells with [D5-ethyl]-tamoxifen resulted in a 2- to 3-fold decrease, compared with tamoxifen, in the number of micronuclei induced in cells arrested in cytokinesis by cytochalasin-B. Further evidence is provided by UV irradiation of the major hepatic DNA adducts isolated from tamoxifen-treated rats, which caused a large shift in the chromatographic mobility of the adducts, consistent with the presence of a 1,2-olefinic linkage in the tamoxifen residue of the adduct leading to cyclization to a phenanthrenylic compound, and consistent with this adduct having arisen from reaction with DNA at the alpha-position of tamoxifen. Taken together, these data strongly suggest that tamoxifen is metabolized to a liver carcinogen by alpha-hydroxylation of its ethyl group.
Carcinogenesis 1994 Aug
PMID:Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates alpha-hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. 805 24

We previously identified, through differential screening of a human primary liver cancer library, a novel gene (named HIP) the expression of which is markedly increased in 25% of human primary liver cancers. HIP mRNA expression is tissue specific since it is restricted to pancreas and small intestine. HIP protein consists in a signal peptide linked to a carbohydrate-recognition domain (CRD), typical of C-type lectins without other binding domains. We have proposed that HIP and related proteins belong to a new family of C-type lectins. Drickamer [Drickamer, K. (1993) Curr. Opin. Struct. Biol. 3,393-400] included this group of proteins in his classification of C-type lectins as the free CRD (group VII) lectins. In the present report we describe the genomic organization and the chromosomal localization of HIP. We have shown that HIP is in fact the pancreatitis-associated protein (PAP) and provided a phylogenetic analysis of the free CRD lectins. Furthermore, the analysis of HIP/PAP gene indicates that the HIP/PAP CRD is encoded by four exons, a pattern shared with all members of this group of proteins. This common intron-exon organization indicates an ancient divergence of the free CRD-lectin group from other groups of C-type lectins. We provide evidence for the localization of HIP/PAP on chromosome 2, suggesting previous duplication of HIP/PAP and the related reg I alpha and reg I beta genes from the same ancestral gene. Finally, the sequence of the 5' upstream region of the HIP gene shows several potential regulatory elements which might account for the enhanced expression of the gene during pancreatic inflammation and liver carcinogenesis.
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PMID:Structural organization and chromosomal localization of a human gene (HIP/PAP) encoding a C-type lectin overexpressed in primary liver cancer. 807 48

The potential carcinogenic effects of internally deposited alpha-particle-emitting nuclides, notably plutonium, in the liver in humans are unknown but are of concern in relation to exposures from the nuclear industry. However, patients injected with the radiographic contrast medium Thorotrast are chronically exposed to alpha-particle radiation from 232ThO2 in the liver. Among 1003 patients injected with Thorotrast, 584 of whom were alive 15 years after the injection and 40 at the end of follow-up, a total of 127 liver cancers were diagnosed, 45 of which were hepatocellular carcinomas, 41 cholangiocarcinomas and 33 hemangiosarcomas. The median time from injection to diagnosis was 35 years (range 18-48) and the cumulative frequency was 55.4% after 48 years. In univariate and multivariate analyses, the cumulative frequency of liver cancer was best described as a function of the estimated mean cumulative alpha-particle radiation dose to the liver 15 years ago, being independent of age, gender and volume of injected Thorotrast. This may be interpreted to mean that the liver cancer rate is not related to the dose rate and that the period from malignant transformation to diagnosis of cancer is 15 years. The risk of liver carcinogenesis induced by alpha-particle radiation, assuming 15 years from induction to diagnosis, was estimated to be 712 cases/10(4) persons per gray. This value is considerably higher than estimated earlier.
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PMID:Primary liver tumors among Danish patients exposed to Thorotrast. 813 50

The rapidly expanding understanding of the progressive processes of carcinogenesis provides opportunities for the identification of molecular biological markers reflecting events from exposure through clinical disease. These molecular biological markers can be classified into categories of markers of exposure reflecting the dose of toxic agents, markers of effect indicating a biological response to exposure, and markers of susceptibility providing information about the inherent sensitivity of individuals to the toxic agents. By definition some of these markers are chemical agent specific, such as a carcinogen-DNA or -protein adduct, while others are biological process specific, such as the altered expression of a gene. This article reviews the development and validation of molecular biomarkers of aflatoxins using experimental and human population studies. The development of molecular biomarkers for aflatoxins is based upon the extensive research database available about their metabolism, macromolecular adduct formation, and general mechanisms of action. The long-term goal of the research described in this paper is the application of aflatoxin biomarkers to the development of preventive interventions in human populations at high risk for liver cancer.
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PMID:Molecular biomarkers for aflatoxins and their application to human cancer prevention. 813 10

Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci or hepatic cancer were determined. The doses ranged from 1 ng (TCDD) to 400 mg (chloroform). In mouse skin, 10 dose-response studies of 4 promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], anthralin, chrysarobin, and 2,6-di-tert-butyl-4-hydroperoxyl-2,5-cyclohexadienone [BHTOOH]) were selected. In these mouse skin studies the doses ranged from 0.425 nmole (TPA) to 20,000 nmole (BHTOOH) per mouse. The length of time promoters were applied to the skin varied between 15 and 60 weeks. Either skin papillomas or carcinomas were determined. The dose-response relationships are presented on the basis of moles of promoter, percentage of the fully effective promoting dose, or percentage of the acute oral rat LD50. The degree of concavity of the dose-response curves was determined. The available dose-response data are critiqued and discussed on the basis of future research needs for biologically based cancer risk assessment models.
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PMID:Dose-response relationship in multistage carcinogenesis: promoters. 818 17

Liver cell proliferation is a complex process that can be affected by a large number of factors such as bile acids, which have been reported to be associated to the pathogenesis of liver cancer. In this work, bile acid-induced modifications in DNA synthesis by regenerating perfused rat liver were investigated. Two-thirds hepatectomy was carried out 24 hr before perfusion of liver with recirculating, erythrocyte-free Krebs-Henseleit solution. The viability of the preparations was maintained under all experimental conditions, as indicated by bile flow, oxygen uptake, perfusion pressure, perfusion flow and release of lactate dehydrogenase and potassium into the perfusate. Livers received (min 10 to min 60) bile acid infusion at a rate of 25 nmol/min/gm liver (i.e., maximal secretion rate/2) in regenerating livers as calculated for taurocholate in separate experiments). Trace amounts of [methyl-14C]thymidine were added to the perfusate at min 30. At the end of the experiments (min 60) the livers were washed, removed, weighed and homogenized to determine radioactivity in whole tissue, in DNA and in non-DNA-related fractions. Taurocholate and, to a lesser extent, taurodeoxycholate and dehydrocholate (but not ursodeoxycholate) were found to reduce 14C incorporation into DNA. This was not due to changes in the content of 14C in whole, regenerating liver tissue. Taurocholate, taurodeoxycholate, dehydrocholate and ursodeoxycholate had no effect on thymidine uptake; moreover, the proportion of 14C found in bile was negligible. However, bile acid-induced modification in the fate of intracellular thymidine was observed. In regenerating livers receiving no bile acid, the 14C carried by thymidine metabolites accounted for about 60% of 14C in whole liver tissue. Taurocholate markedly increased this proportion to about 80%. Reverse-phase high-pressure liquid chromatography revealed that most of this 14C (about 80%) was recovered at the elution time, corresponding to thymidine catabolites rather than to DNA precursors. These results suggest that bile acids induce enhancement of thymidine catabolism that reduces its incorporation into DNA; inhibition in the process of DNA synthesis itself, leading to a subsequent increase in the metabolism of DNA precursors; or both. Moreover, from the diversity in this property for bile acid species it might be inferred that changes in the composition and size of the bile acid pool during liver carcinogenesis or regeneration play a role in the modulation of the proliferative process.
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PMID:Bile acid-induced modifications in DNA synthesis by the regenerating perfused rat liver. 822 25

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

Previous studies have demonstrated that ingestion of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) during the aflatoxin B1 (AFB1) treatment phase completely prevented hepatic cancer. In this study we evaluated the effect of feeding oltipraz during the post-AFB1 treatment phase. Fifty-five male F344 rats were divided into five groups. All rats were gavaged with 25 micrograms AFB1/rat, five times a week for two successive weeks. The rats were fed the oltipraz-supplemented diet according to three different feeding regimes: during the AFB1 treatment phase (1 week prior to, during and 1 week after the last gavage with AFB1); during the post-treatment phase; or throughout the entire time of the experiment. Phenobarbital-supplemented diet was fed during post-treatment phase to one group and this was used as a positive control for the promotion of AFB1-induced focal growth. The burden of putative, preneoplastic, hepatic glutathione S-transferase P-positive foci was evaluated at 13 weeks after the AFB1 treatment phase. As seen previously, oltipraz fed during the AFB1 treatment phase significantly inhibited focal development, i.e. the volume percent of the liver occupied with foci was reduced by 87%. Oltipraz when fed during the post-treatment phase neither inhibited nor enhanced focal development.
Carcinogenesis 1993 Nov
PMID:Evaluation of the post-initiation effects of oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. 824 75


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