Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The title compounds (14a,b) were 5' epimers of a derivative of a phosphonate isostere of ATP in which the CH2OP alpha system of ATP was replaced by CH(R)CH2P alpha [R = L-S(CH2)2CH(NH2)CO2H]. They resisted synthesis via attempted S-alkylation of the corresponding epimeric 5'-mercapto derivatives. A practicable route to 14a,b commenced with Michael condensation of L-homocysteine with the diphenyl ester of the 5',6'-vinyl phosphonate analogue of 2',3'-O-isopropylideneadenosine 5'-phosphate. The resulting epimeric 5' thioethers were separated by reverse-phase HPLC. The two phenyl groups were replaced by benzyl groups, after which the alpha-amino acid residue was protected as an N-Boc methyl ester. Both benzyl groups were removed by hydrogenolysis, and the resulting phosphonic acid was converted into its pyrophosphoryl derivative. Blocking groups were then removed under conditions that furnished 14a and 14b without racemization of their L-amino acid residues. Also synthesized were the P beta-NH-P gamma imido analogue (15a) of 14a and the sulfoxide derivative (16a) of 14a. The structures of 14a and 16a were verified by FAB mass spectra, which revealed the protonated molecular ions of their sodium salts. All adducts appeared to function as dual substrate site inhibitors (competitive to ATP and to methionine) of the rat normal tissue (MAT-2) form of methionine adenosyltransferase (MAT); 14a and 15a [KM(ATP)/Ki = 4 and 9, respectively] were the most effective. Adduct 15a was the most effective inhibitor [KM(ATP)/Ki = 13] of the MAT-T form from rat hepatoma tissue; the kinetic data indicated dual-site inhibition by 15a with apparently complete coverage of the ATP site and incomplete coverage of the methionine site. The inhibition properties of the adducts indicated little preference in the order in which the two MAT forms bound ATP and methionine.
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PMID:Isozyme-specific enzyme inhibitors. 11. L-homocysteine-ATP S-C5' covalent adducts as inhibitors of rat methionine adenosyltransferases. 348 76

The livers from five vinyl chloride workers are described. They show angioformative and hepatocellular growth disturbance in varying proportions: angiosarcoma in four cases, liver cell hyperplasia in all, hyperplastic nodules in three cases and hepatocellular carcinoma in two cases. In one case the transition between hyperplastic nodule and hepatocellular carcinoma is demonstrated. The relationship between these changes and vinyl chloride exposure is discussed, with evidence that they are causally related.
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PMID:Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. 619 69

Six hepatic angiosarcomas, one hepatoma and one hepatic "fibrosis" with portal hypertension in patients chronically exposed to vinyl chloride monomer (VCM) are reported. The industrial methods of synthesis and current knowledge concerning the carcinogenic role of VCM are reviewed. Histogenetic and pathogenetic concepts of "fibrosis" and angiosarcomas of liver are exposed.
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PMID:[Hepatic lesions caused by vinyl chloride monomer in humans. Study of eight clinicopathological cases (author's transl)]. 625 69

Four treatment groups (80 male Sprague-Dawley rats/group) were used in a 2 X 2 factorial design: inhalation of 600 ppm vinyl chloride (VC) 4 hr/day, 5 days/week for 1 year; VC and ingestion of 5% ethanol in water (v/v); filtered air and ethanol; filtered air. Ingestion of ethanol was begun 4 weeks prior to inhalation of VC and continued for life or termination of the study at two and one-half years from the first VC exposure. In this model system, ethanol potentiated the carcinogenic response to VC in the liver and produced an excess of neoplasms in animals receiving ethanol alone. Inhalation of VC induced angiosarcoma of the liver in 23% of the exposed animals; ethanol in addition to VC inhalation increased the incidence to 50%. Concomitant administration of VC and ethanol also produced an excess of hepatocellular carcinoma and lymphosarcoma. Ethanol with or without VC had a strong tumorigenic effect on the endocrine system. These results indicate that ethanol is a cocarcinogen in relation to the carcinogen VC.
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PMID:Effect of ethanol on vinyl chloride carcinogenesis. 627 14

Hepatocellular carcinoma was diagnosed already during life in a 54-year-old workman who had been exposed to high concentration of vinyl chloride due to his occupation for more than twenty years. In addition, typical early changes as seen in experimental vinyl chloride induced angiosarcoma were observed. In recent years permissible room air concentration of vinyl chloride at work have been lowered drastically. However, due to the long latency occurrence of malignant liver tumours may still be expected in persons exposed formerly. Within the search programme for such patients at risk ultrasonography and computed tomography as non-invasive methods with high accuracy are advisable.
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PMID:[Hepatocellular carcinoma after exposure to vinyl chloride]. 630 98

Histologic sequences in the liver of rodents exposed by inhalation to gaseous vinyl chloride were compared to the lesions in man exposed to the same agent, mainly in vinyl chloride polymerization plants. An identical sequence, starting with circumscribed proliferation of hepatocytes, soon followed by proliferation of a variety of sinusoidal cells and frequently associated with sinusoidal dilatation, progresses to intralobular and more frequently to trabecular angiosarcoma. Predominantly in young animals and rarely in man, hepatocellular carcinoma develops, but never cirrhosis. The sequence represents a dynamic process of competition between proliferating hepatocytes and sinusoidal cells, of hepatocytes with fibroplasia, between perisinusoidal fibrosis and sinusoidal dilatation, and of proliferation of various sinusoidal cells versus angiosarcoma. The great similarity in the evolution in man and rodents, rarely encountered in other experimental models, supports the prediction of human cancer from animal experiments. The precursor nodules differ from the nodules commonly observed in hepatocarcinogenesis by co-proliferation of sinusoidal cells. The differences in the reactions between man and rodents bespeak a strong fibroblastic reactivity in man. Most important, the precursor lesion of mixed hepatocellular and sinusoidal cell proliferation may be of diagnostic value, being superior to conventional hepatic tests in detection of some initial environmental lesions.
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PMID:Vinyl chloride-induced hepatic lesions in man and rodents. A comparison. 689 Oct 14

HAS (hepatic angiosarcoma) has been associated with exposure to vinyl chloride, "Thorotrast," radium inorganic arsenic and androgenic-anabolic steroids. This case reports a possible association between HAS and oral contraceptive steroids. A 42-year old patient presented with a 4-month history of epigastric fullness and symptoms of esophageal reflux. A large epigastric mass from the left lobe of the liver was revealed at physicial examination. The patient had been taking oral contraceptives for 10 years but discontinued its use the year before after a hysterectomy for uterine fibroids. She consumed 10 g/week of alcohol, and smoked 10 cigarettes a day. There was no previous history of liver disease. A liver scintigram, ultrasonography, and selective hepatic arteriography revealed an avascular mass in the left lobe of the liver. Laparotomy was performed, revealing a huge, partly cystic and irregular mass in the left lobe of the liver, adhering to the stomach and transverse colon. Multiple biopsies showed the mass to be largely necrotic, and features of the viable portions were highly suggestive of HAS. She died 3 1/2 weeks after the procedure. At autopsy, histological examination confirmed the diagnosis of HAS, as well as the metastatic deposits in the diaphragm, small bowels, pancreas, adrenal, lung and pleural cavities. Although it is not known whether oral contraceptive use is definitely related to the development of liver tumor in this patient, there has been evidence suggesting that oral contraceptive steroids may induce the tumor-precursor stage observed after exposure to agents which are accepted as causing HAS. If an association between oral contraceptive use and HAS is established, it will confirm the hypothesis of Falk et. al. that certain environmental agents produce a tumor-precursor lesion which can develop into adenoma, hepatocellular carcinoma, or HAS.
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PMID:Possible association of angiosarcoma with oral contraceptive agents. 719 76

Mutations in the p53 tumor suppressor gene are commonly found in the major human cancers and the mutational spectrum in some cancer types is consistent with the genotoxic effects of the associated environmental risk factors. Thus far there is little information on p53 mutations in cancers of factory workers with a history of carcinogen exposure in the workplace. Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers. Loss of p53 function in osteo- and fibrosarcomas can occur by two different mechanisms, p53 mutation and amplification of the MDM2 gene. We examined tumors from five vinyl chloride-exposed patients, four with ASL and one with hepatocellular carcinoma (HCC), for evidence of MDM2 proto-oncogene amplification or p53 mutation in exons 5-8. Amplification of MDM2 was not found, but in two of the angiosarcomas an A:T to T:A missense mutation was detected. p53 sequence analysis of vinyl chloride associated cancers may provide valuable information on the relationship between carcinogen exposure and DNA damage in cancer-related genes.
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PMID:p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. 829 34

The case of a 71-year-old man with a primary hepatocellular carcinoma in a non-cirrhotic liver is reported. There were no risk factors of hepatocellular carcinoma (HCC)-like liver cirrhosis, alcohol drinking, tobacco smoking, exposure to vinyl chloride, thorotrast, aflatoxin or alpha 1-antitrypsin deficiency. Serologically, the patient was positive for antibodies to the hepatitis B virus (anti-HBc, anti-HBs) and for anti-hepatitis C virus (HCV) antibodies. Virologically, positive and negative strands of HCV RNA could be detected in the patient's serum and tumorous liver tissue by reverse transcription polymerase chain reaction as a sign of persistent HCV replication. Histologically, the HCC was completely surrounded by liver tissue which showed the signs of nodular regenerative hyperplasia. Indeed, the mechanism of hepatocarcinogenesis remains to be clarified. However, this case supports the observation that HCC may also develop in patients with HCV infection without preexisting liver cirrhosis.
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PMID:Hepatitis C virus associated primary hepatocellular carcinoma in a noncirrhotic liver. 838 32

Two quantitative cytotoxicity assay methods (cytoplasmic retention of carboxyfluorescein and mitochondrial cleavage of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)) have been used to evaluate the response of two cultured human cell lines; HepG2 (hepatoma) and W138va13 (transformed lung fibroblasts) to extracts of a range of poly(vinyl chloride) (PVC) formulations. Two plasticizers; di(2-ethylhexyl)phthalate (DEHP) and di-isooctyl phthalate and a range of tin and non-tin stabilizers were incorporated in the study. Only those formulations containing both a plasticizer and a tin-based stabilizer produced extracts which were toxic. Extracts of those formulations which contained both plasticizer and dibutyl tin dimaleate stabilizer were toxic to both cell lines in both assay methods. Extracts of a formulation containing plasticizer and a dioctyl tin mercaptide were toxic to both cell lines in the carboxyfluorescein assay but were only toxic to the WI38va13 cells in the MTT assay. The WI38va13 cells were generally more sensitive to the extracts than the HepG2 cells. When serial dilutions of the extracts were evaluated, the carboxyfluorescein assay proved to be the more sensitive of the two. The acute toxicity of extracts of these PVC formulations cannot be directly attributed to the plasticizers or to the tin stabilizers. It is likely that a synergistic mechanism, such as plasticizer facilitated extraction of the tin stabilizer, exists.
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PMID:Poly(vinyl chloride) formulations: acute toxicity to cultured human cell lines. 856 22


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