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 effects of alpha-difluoromethylornithine (DFMO; RMI 71782) in combination with vindesine or Adriamycin were investigated in three different animal tumor models. When given in a concentration of 2% in drinking water to C57BL/6 X DBA/2 F1 mice inoculated i.p. with L1210 leukemia cells, DFMO prolonged the survival time 1,2-fold. Treatment with vindesine (0.1 mg/kg/week i.p. or Adriamycin (2.5 mg/kg/week i.p.) increased the mean survival time 1.4- and 2.3-fold, respectively. DFMO with vindesine doubled survival time, while DFMO with Adriamycin increased it 3.5-fold and yielded 30% long-term survivors. The growth of solid tumors induced in Buffalo rats by i.m. injection of hepatoma tissue culture cells was inhibited 65% after 2 weeks of DFMO treatment. Similar inhibition of growth could be achieved by weekly i.p. injections of vindesine (0.2 mg/kg) or Adriamycin (2.5 mg/kg). When the same doses of these drugs were administered in combination with DFMO, the growth of this hepatoma was completely arrested. Combined treatment of BALB/c mice bearing s.c. solid EMT6 tumors with DFMO and adriamycin or vindesine also resulted in enhanced inhibition of tumor growth compared to single-drug therapy. These results indicate that combination of DFMO with vindesine or Adriamycin is an effective approach to the treatment of several animal cancers.
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PMID:Effects of alpha-difluoromethylornithine alone and combined with adriamycin or vindesine on L1210 leukemia in mice, EMT6 solid tumors in mice, and solid tumors induced by injection of hepatoma tissue culture cells in rats. 679 66

The quassinoids (brusatol, bruceantin, bisbrusatolyl esters, and bisbruceantinyl esters of succinic and malonic acids) were observed not to be universal protein synthesis inhibitors. Rather, they were selective for both the types of cancers, e.g., P-388 lymphocytic leukemia, Ehrlich and hepatoma carcinoma and L-1210 lymphoid leukemia, as well as types of normal tissues (e.g., lymphocytes), in which they demonstrated protein synthesis inhibition. The data suggest that the observed difference in the magnitude of protein synthesis inhibition of two P-388 lymphocytic leukemia cell lines by the quassinoids was at the ribosomal levels, whereas the observed difference in normal livers from various strains of mice involve differences in cell membrane transport of the quassinoids into the various tissues. Detailed studies indicated that the mode of action of the quassinoids as protein synthesis inhibitors was identical in all of the cells where inhibition was observed; i.e., the elongation step of protein synthesis was blocked by the quassinoids. The data derived from assays for polyuridine-directed polyphenylalanine synthesis of isolated ribosomes demonstrated that the ID50 values obtained were consistent with the observed inhibition of whole cell protein synthesis inhibition for P-388 cells, as well as for BDF1 and DBA/2 liver cells. The ID50 values obtained from various cells, e.g., P-388 cells and normal liver, were all in the microM range and are consistent with previously published values for the quassinoids in the rabbit reticulocyte and yeast systems.
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PMID:Antitumor agents LIX: effects of quassinoids on protein synthesis of a number of murine tumors and normal cells. 687 23

We have studied the induction of a granulocyte-associated leukocytosis (leukemoid reaction) in C3HA, C57B1/6, and DBA/2 mice by a number of transplantable tumors of different origin. Leukemia L1210, Hepatoma 22, a transplantable mammary carcinoma of spontaneous C3HA origin, and a L929 culture fibroblasts-derived rhabdomyosarcoma, all induced a leukemoid reaction in their specific mouse strain. Melanoma B16 and Lewis lung carcinoma gave no reaction; Adenocarcinoma 755 and Harding-Passey melanoma evoked a leukocytosis but not due to an increase in neutrophils. Some extratumoral factors can influence the hematological response; the intensity of final leukemoid reaction was higher in female mice than in males bearing the same tumor. On the other hand, Ehrlich ascites tumor transplanted in all three inbred mouse strains rendered different levels of leukemoid reaction; response was higher in DBA/2, intermediate in C3HA and lower in C57B1/6.
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PMID:Leukemoid reaction induced by different transplantable tumors in three inbred mouse strains. 707 May 57

The capacity of 19 polycyclic aromatic compounds and 15 benzo[a]pyrene metabolites to displace [1,6-3H]2,3,7,8-tetrachlorodibenzo-p-dioxine ([3H]TCDD) from the mouse liver cytosolic Ah receptor was examined. We compared our data with various parameters taken from previously published results: the capacity of seven polycyclic hydrocarbons to induce aryl hydrocarbon hydroxylase (AHH) activity in human cell cultures, the capacity of 10 polycyclic hydrocarbons to induce azo dye N-demethylase activity in rat liver, the capacity of 6 polycyclic hydrocarbons to shorten zoxazolamine paralysis times in the intact rat, and the capacity of 15 benzo[a]pyrene metabolites to induce AHH activity in rat hepatoma H-4-II-E cultures. An excellent correlation is seen between the capacity to displace the radioligand from the Ah receptor and the capacity to induce these monooxygenase activities. differences in the rate of cellular uptake and formation of alkali-extractable metabolites of dibenzo[a,h]anthracene, 3-methylcholanthrene, and benzo[a]anthracene in Hepa-1 mouse hepatoma cell cultures do not account for differences in the capacity of these three polycyclic hydrocarbons to displace [3H]TCDD from the Ah receptor.
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PMID:The Ah regulatory gene product. Survey of nineteen polycyclic aromatic compounds' and fifteen benzo[a]pyrene metabolites' capacity to bind to the cytosolic receptor. 708 63

The metabolic activation of the potent carcinogen dibenzo[a,h]anthracene (DB[a,h]A) was investigated with recombinant human cytochrome P450 enzymes 1A2, 2B6, 2C8, 2C9, 2E1, 3A3, 3A4, and 3A5 expressed in hepatoma G2 cells and with 14 different human liver microsomes. Three dihydrodiols, three phenols, and one diphenol were formed and separated by high-performance liquid chromatography and identified by UV absorption and mass spectra. Of all P450s tested, 1A2 and 2C9 were the most active and 2B6 was moderately active in the rate of total DB[a,h]A metabolism (2.5- to 12-fold greater activity than that for other P450s). The trans-3,4-dihydrodiol, generally recognized as a precursor of the ultimate carcinogenic 3,4-diol-1,2-epoxides, was produced most actively by 2C9, then 1A2 and 2B6. The values of enzymatic kinetics (K(m) and V(max)) indicated that 2C9 had the highest catalytic efficiency (V(max)/K(m) = 9.7) in the formation of 3,4-dihydrodiol, in contrast to 1A2 (5.9) and 2B6 (4.4). 1A2 had the highest activity toward production of the 1,2-dihydrodiol, which is considered to be a weakly carcinogenic metabolite. Although specific activities of human liver microsomes in overall metabolism of DB[a,h]A markedly differed between individuals, metabolic patterns were observed similar to that generated from 1A2. Since human 1A1, a predominant enzyme for metabolism of polycyclic aromatic hydrocarbons, is not significantly expressed in the liver, hepatic microsomal 2C9, 1A2, and 2B6 all probably contribute to the metabolic activation of DB[a,h]A.
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PMID:Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450. 863 31

Cigarette smoke is known to induce cytochrome P4501A1 expression and activity in a variety of species. Although the elevation of this isozyme is assumed to be associated with the activation of the CYP1A1 gene through a ligand-mediated mechanism involving the Ah-receptor (AhR), this has not been determined. In this study we have examined the mechanism by which an ambient level of aged and diluted sidestream cigarette smoke (ADSS) induces cytochrome P4501A1. Effects of ADSS on C57BL/6N and DBA/ 2N mice were examined. Induction of P4501A1-associated ethoxyresorufin-O-dealkylase (EROD) activity was observed in the lungs of C57BL/6N mice, while there was no induction in DBA/ 2N mice. ADSS also induced EROD in wild-type mouse hepatoma (Hepa1c1c7) cells (hepa1), but not in variant hepa1 cells defective in the AhR nuclear translocator (ARNT) protein. ADSS exposure of recombinant hepa1 cells, stably transfected with a reporter plasmid containing the luciferase gene under control of several dioxin responsive enhancers (DREs), resulted in a time- and exposure-dependent induction of luciferase activity. ADSS-mediated induction of luciferase activity was inhibited by alpha-naphthoflavone (alpha NF), an Ah-receptor antagonist. Gel retardation analysis demonstrated that exposure to ADSS induced transformation and DNA binding of the AhR complex. In summary, our results not only indicate a role for the AhR in mediating the induction of P4501A1 by ADSS, but also demonstrate that environmentally relevant levels of ADSS must contain AhR ligands at sufficient concentrations to activate gene expression in an AhR-dependent manner.
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PMID:Ah-receptor-dependent modulation of gene expression by aged and diluted sidestream cigarette smoke. 891 78

The H4IIE rat hepatoma cell bioassay has been extensively used to assess the toxic equivalents (TEQs) of complex mixtures of halogenated aromatic hydrocarbons in environmental samples. However, there is often a discrepancy between bioassay induction results and toxic equivalents calculated from chemical analysis of samples; the former generally yield higher bioassay-TEQs. Polynuclear aromatic hydrocarbons (PAHs) are a class of chemicals which can significantly contribute to induction-TEQs. Benzo(a)pyrene (BAP), dibenz(a, h)anthracene (DBA), benz(a)anthracene (BA), benzo(k)fluoranthene (BkF), benzo(b)fluoranthene (BbF), chrysene (Chr), and indeno(1,2,3-c,d) pyrene (IdP) are carcinogenic PAHs found in environmental samples, including oysters collected from Galveston Bay. The induction potency of these PAHs relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was determined individually in rat hepatoma H4IIE cells seeded in 6-well plates, and the induction-derived equivalency factors (EFs) relative to TCDD were 0. 000354, 0.00203, 0.000025, 0.00478, 0.00253, 0.00020, 0.0011 for BAP, DBA, BA, BkF, BbF, Chr, and IdP, respectively. Dilutions of a reconstituted PAH mixture containing 23 PAHs (744 to 4466 ng/g total PAHs) with constant percentages of BAP (4.5%), DBA (3.5%), BA (2.4%), BkF (3.7%), BbF (3.5%), Chr (4.7%), and IdP (4.2%) yielded bioassay-derived induction-EQs that ranged from 0.52 to 1.44 ng/g. Oysters exposed in the laboratory to the same PAH mixture for 30 days differentially accumulated the PAHs with time. Bioassay-EQs for these oyster extracts ranged from 0.94 to 5.79 ng/g. These results were similar to the chemically calculated EQs which varied from 0.81 to 3.13 ng/g.
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PMID:Characterization of the H4IIE rat hepatoma cell bioassay for evaluation of environmental samples containing polynuclear aromatic hydrocarbons (PAHs). 917 14

The hepatic cytochrome P4502A6 (CYP2A6) enzyme mediates the oxidative metabolism of several procarcinogens that have liver as their primary target. Mouse models indicate that liver tumors invariably overexpress CYP2A forms, and that inflammation and cirrhosis may regulate the CYP2A expression pattern. In this study, the distribution of the CYP2A6 protein was investigated in a series of 24 human hepatocellular carcinoma (HCC) samples by immunohistochemical analysis. A polyclonal antibody was raised in chicken against CYP2A5, the mouse orthologue of CYP2A6. The antibody was characterized and found to be specific for CYP2A members. In DBA/2 mouse liver, a strong increase of CYP2A5 protein amount, localized in the perivenous region, occurred in response to treatment with pyrazole. In human HCC samples, overexpression of CYP2A6 protein was associated with the presence of chronic inflammation and cirrhosis. CYP2A6 protein was observed in 9 of 16 (56%) of samples with non-neoplastic hepatocytes and in 10 of 24 (42%) HCC samples. The staining for CYP2A6 protein was very heterogeneous in tumor cells, suggesting that increased expression of CYP2A6 occurred in a distinct subpopulation of neoplastic cells. In Kaplan-Meyer survival analysis, there was a tendency toward a more favorable prognosis in patients with CYP2A6-positive tumors in comparison with patients with CYP2A6-negative tumors. These data suggest that, in human HCC, in contrast to mouse liver tumors, CYP2A6 overexpression is not an invariable phenotype.
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PMID:Cytochrome P4502A6 (CYP2A6) expression in human hepatocellular carcinoma. 946 41

As part of a continuing program aimed at developing nonpolyglutamylatable inhibitors of dihydrofolate reductase that are less toxic and more specific in their action, we herein report the therapeutic efficacy and toxicity of gamma-methylene-10-deazaaminopterin (MDAM) in athymic nude mice bearing advanced human HCT-8 ileocecal xenografts and its antitumor activity in C57BL/6 x DBA/2 F1 (hereafter called B6D2F1) mice bearing P388 murine leukemia. For the xenograft study, MDAM was administered at the maximum tolerated dose by the following dose schedules: (a) 5-day continuous i.v. infusion at 1.0 mg/kg/day (schedule I); and (b) i.v. push, daily for 5 days at 50 mg/kg/day (schedule II). The maximum tolerated dose values for methotrexate (MTX) under these conditions were 0.2 and 1.0 mg/kg/day for schedule I and schedule II, respectively. MTX did not exhibit any significant antitumor activity in this model system by both schedules; however, MDAM induced complete responses of 13 and 25% and partial responses of 25 and 50% by schedules I and II, respectively. MDAM also exhibited antitumor activity significantly superior to that of MTX in the P388 tumor model. One of the enantiomers of MDAM, which possesses the natural configuration at the gamma-methyleneglutamate moiety (l-MDAM), has been shown to be a better inhibitor of human recombinant dihydrofolate reductase and H35 hepatoma cell growth than D,L-MDAM. L-MDAM inhibited the uptake of radiolabeled folinic acid to H35 hepatoma cells eight times more efficiently than MTX. The results indicate that the superior activity of MDAM relative to MTX may be partially due to a combination of enhanced transport to tumor cells and slower deactivation by aldehyde oxidase.
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PMID:Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity. 981 21

The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B(1) (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis.
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PMID:Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. 1290 37


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