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

Antibiotic C3368-A (CA) is produced by a fungus strain from a soil sample collected in Antarctica. CA markedly inhibited radiolabeled thymidine and uridine transport in mouse Ehrlich carcinoma cells, its 50% inhibitory concentration (IC50) being 4.6 and 7.7 microM, respectively. In clonogenic assay, CA displayed a synergistic effect with methotrexate (MTX), mitomycin C (MMC), 5-fluorouracil (5FU), and Adriamycin (ADR) against human oral epidermoid carcinoma KB cells. CA also markedly enhanced the inhibitory effect of 5FU and ADR on the proliferation of human hepatoma BEL-7402 cells as determined by the p-nitrophenyl-N-acetyl-beta-D-glucosaminide (NAG) enzyme-reaction assay. 5FU or ADR cytotoxicity was not augmented by CA in human fetal lung 2BS cells. In vivo, CA significantly potentiated the inhibitory effect of MMC against colon carcinoma 26 in mice. No significant augmentation of toxicity by the combination was found in treated mice. The results suggest that CA, the newly found nucleoside-transport inhibitor, may be useful in potentiation of the effect of antitumor drugs.
 ...
PMID:Antibiotic C3368-A, a fungus-derived nucleoside transport inhibitor, potentiates the activity of antitumor drugs. 776 52

The in vitro experiment was carried out following 32P-postlabeling analysis to determine the DNA-reactive bile acids present in the human body. The unconjugated and conjugated forms of cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA) and lithocholic acid (LCA) were added to calf thymus DNA followed by 1 h of incubation at 37 degrees C. After the incubation the mixture was analyzed by the nuclease P1 modification of 32P-postlabeling. Among the 12 bile acids tested, our results showed that unconjugated CDCA and LCA and the glycine and taurine conjugates of LCA (g-LCA, t-LCA) were able to bind covalently with naked DNA in vitro without intervention of any catalyst. It was also shown that bile acid alone did not give any spot on TLC. These binding reactions depended on the bile acid concentration in a linear manner. The data on the extent of binding at a concentration of 0.1 mg/ml showed values of 28.5 (t-LCA), 23.7 (g-LCA), 3.47 (LCA) and 1.32 (CDCA) adducts per 10(8) nucleotides. These reactive bile acids were also incubated with COLO 205 human colon carcinoma cells and Hep G2 human hepatocellular carcinoma cells for 24 h, but no specific DNA adduct was formed. Further, when LCA or CDCA was administered into male Fischer 344 rats by gavage at a dose of 10 mg/rat every 8 h for 3 days, no specific DNA adduct was detected in their liver or colon. Covalent DNA adducts are believed to cause alteration of the primary structure of genes, which is potentially linked to carcinogenesis. Though our preliminary data failed to detect any bile acid-related DNA adducts in the cultured cells or in rats, the results may provide a basis for assuming some of these bile acids to be potential initiators of colon cancer.
 ...
PMID:In vitro formation of DNA adducts with bile acids. 792 85

Biliary glycoprotein (BGP) isoantigens are derived by alternative splicing from a single gene and are the human homologs of rat C-CAM and the mouse Bgp species. These glycoproteins represent a family of cell-adhesion molecules. The mouse Bgp isoforms also act as receptors for the hepatitis viral capsid-protein. BGP is a member of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin supergene family, yet it displays restricted expression patterns and unique functions. Since the loss or reduced expression of BGP is associated with human colorectal carcinomas, the elements in its upstream regulatory region were analyzed. A cluster of transcriptional initiation sites and the minimal promoter, located within 150 bp upstream of the major transcriptional start site, were active in human colon carcinoma and hepatoma cells. Unlike the CEA gene, BGP gene transcription was not modulated by a silencer region; repetitive elements in the BGP upstream region were not involved in activation or repression. Footprinting experiments identified two cis-acting elements and mobility-shift assays demonstrated that these elements bound several transcription factors, among them, USF, HNF-4 and an AP-2-like factor. In cotransfection experiments, both the USF and HNF-4 transcription factors transactivate the BGP gene promoter and compete for the same regulatory element. The Sp1 transcription factor, shown to be involved in CEA gene transcriptional regulation, does not bind to the BGP gene promoter. We, therefore, propose that the relative distributions and interactions of these transcription factors mediate distinct transcriptional regulation of the BGP gene in colon and liver; this regulation could be distorted during the oncogenic process.
 ...
PMID:Transcriptional control of the human biliary glycoprotein gene, a CEA gene family member down-regulated in colorectal carcinomas. 805 23

7-N-((2-([2-(gamma-L-Glutamylamino)ethyl]dithio)ethyl))mitomycin C (KW-2149) is an analogue of mitomycin C (MMC) and has prominent activities against various tumors. We studied the antitumor effects of KW-2149 in MMC-resistant variants of human colon carcinoma HT-29 (HT-29/MMC) and mouse hepatoma Hepa-I (C4, B13NBii1) cells, which are deficient in DT-diaphorase and cytochrome P450 reductase, respectively. These enzymes mediate the reductive activation of MMC in the cells. Although HT-29/MMC and C4, B13NBii1 cells showed significant resistance to MMC, they showed sensitivity tl KW-2149 comparable to their parental tumors, indicating that DT-diaphorase and cytochrome P450 reductase could not be involved in the activation of KW-2149. In studying the activation mechanism of KW-2149, we found that glutathione (GSH) and cysteine significantly enhanced the cytotoxicity of KW-2149 in HT-29 cells. The DNA adduct of KW-2149 was increased when HT-29 cells or the isolated nuclei of the cells were incubated with KW-2149 in the presence of physiological concentrations of GSH and cysteine. KW-2149 alkylated calf thymus DNA in the presence of GSH and cysteine in vitro. These results indicate that activation of KW-2149 by thiol molecules, unlike MMC, could be an important activation mechanism of KW-2149 to form DNA adduct and to exert its cytotoxicity. This is the reason why KW-2149 is effective against MMC-resistant tumors with deficiencies in the MMC activation enzymes.
 ...
PMID:Nonenzymatic reductive activation of 7-N-((2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl))mitomycin C by thiol molecules: a novel mitomycin C derivative effective on mitomycin C-resistant tumor cells. 816 87

In areas of the world where hepatitis B and aflatoxin ingestion are common, alterations of the p53 tumor suppressor gene have frequently been reported in hepatocellular carcinoma (HCC). In particular, G-to-T transversions at codon 249 of the p53 gene have been consistently observed in hepatocellular carcinomas in China and sub-Saharan Africa. The goal of this study was to determine the frequency and relationship of p53 gene alterations and hepatitis B in formalin-fixed, paraffin-embedded HCCs resected in the United States. Since immunoreactivity for p53 correlates closely with the presence of missense mutations in the p53 gene, we performed immunohistochemical staining with the monoclonal antibody PAb1801. Only seven of 37 cases (19%) demonstrated nuclear accumulation of p53 gene product, in contrast to 10 of 20 cases (50%) of colon carcinoma metastatic to the liver. Staining was not observed in seven liver cell adenomas, 10 cases of focal nodular hyperplasia, or eight cases of cirrhosis. DNA was extracted from formalin-fixed paraffin sections for additional analysis with use of the polymerase chain reaction (PCR). G-to-T transversions of the third nucleotide of codon 249 were demonstrated in only four of 37 cases (11%), three of which had stained with PAb1801. Of 13 patients for whom there was information about a restriction fragment length polymorphism (RFLP) for BstUI within the fourth exon of the p53 gene, allelic loss of p53 was demonstrated in only two cases (15%), both of which stained with PAb1801. Because of previous reports specifically associating hepatitis B with p53 mutations in HCC, we performed nested PCR for hepatitis B virus DNA. Five of 37 cases (14%) contained hepatitis B virus DNA, two of which stained diffusely for p53 and three of which had codon 249 mutations. Our findings indicate that alterations in the p53 gene, particularly at codon 249, are uncommon in HCCs in the United States, and when present are associated with hepatitis B. Since hepatitis B is infrequently associated with HCC in our patient population, the role of p53 alterations in hepatocellular carcinogenesis may not be as significant as in other parts of the world where hepatitis B and aflatoxin are more prevalent.
 ...
PMID:Hepatitis B and alterations of the p53 tumor suppressor gene in hepatocellular carcinoma. 823 31

The process of freezing in normal human livers and in human liver tumors was studied by freezing samples of these tissues with constant cooling rates and then examining the morphology of the frozen tissue, after freeze substitution, with the light microscope. Cooling rates varied from 2 degrees C/min up to approximately 2000 degrees C/min. It was observed that high cooling rates produce extensive intracellular ice in both normal and neoplastic liver. At slow rates of cooling, normal and neoplastic liver cells dehydrated and large extracellular ice crystals formed. Comparison of the frozen normal liver and the frozen malignant tumors shows that for the same rates of freezing, the tumor cells retain more cellular water and therefore show less susceptibility to dehydration at low rates of cooling. At slow cooling rates, the amount of cellular dehydration and consequent vascular and interstitial space engorgement changed with the type of tissue frozen. The greatest amount of dehydration occurred in normal human liver, followed by metastatic colon carcinoma and finally primary hepatocellular carcinoma. These results are important for cryosurgery since they suggest that malignant tissues have a different response to freezing than normal tissues.
 ...
PMID:A morphological study of cooling rate response in normal and neoplastic human liver tissue: cryosurgical implications. 825 16

The process of cancer metastasis consists of a series of steps resulting in the spread of malignant cells beyond the site of origin and formation of metastases in distant organs. The outcome of this nonrandom process depends, in part, on the interaction of unique tumor cells with a compatible organ microenvironment. The molecular basis of the intrinsic capacity of distinct malignant cells to colonize specific organs and the degree to which host factors influence this process is under intense investigation. Biological analyses of human colon carcinoma tumors obtained from surgical specimens and implanted orthotopically into athymic nude mice revealed that these tumors are heterogeneous for metastatic properties. Moreover, recent evidence using this model suggest that whereas nonmetastatic and highly metastatic cells can grow at local sites, growth in the secondary liver-specific site was associated only with highly metastatic HCC cells. These cells also respond to mitogenic signals produced by damaged normal tissues, suggesting that physiological signals can be utilized by neoplastic cells. Molecular characterization of highly metastatic HCC cells selected in the nude mouse model as well as in situ mRNA hybridization of archival HCC surgical specimens for specific growth factor receptors correlated with the malignant cell's ability to respond to organ-specific growth factors. This article will focus on biological and molecular evidence supporting the hypothesis that organ-derived, paracrine growth factors regulate the site-specific growth of receptive malignant cells that possess the appropriate receptors.
 ...
PMID:Paracrine growth regulation of human colon carcinoma organ-specific metastasis. 828 17

The biological activity of many cytokines is regulated by binding proteins present at the cell surface, in extracellular matrices or in soluble phase. We describe here a TGF-beta binding protein that is both an extracellular matrix and a cell surface protein. When intact extracellular matrices of HEP-G2 cells were affinity cross-linked with 125I-TGF-beta 1, two major binding components were seen: a 250-kD, proteoglycan-like molecule, presumed to be betaglycan, and a 60-kD protein. The 60-kD TGF-beta-binding protein was also present at the cell surface. It could be released from the cell surface by treating cells with high salt, heparin, chondroitin sulfate, heparitinase, or chondroitinase, indicating that it is bound to heparan sulfate and chondroitin sulfate proteoglycans. The 60-kD protein bound TGF-beta 1 with an apparent dissociation constant of 1.6 nM, and there were 30,000 binding sites per cell at the cell surface. In addition to the HEP-G2 cells and another hepatoma cell line, the 60-kD protein was also found in a human colon carcinoma (HT-29) cell line but not in rat kidney (NRK-49F) or human fibroblast (HUT-12) cell lines. The 60-kD protein could be extracted from cells containing it and transferred to the surface of previously negative cells. The 60-kD protein may serve to regulate the binding of TGF-beta to its signal transducing receptors by targeting TGF-beta to appropriate locations in the microenvironment of cells.
 ...
PMID:A 60-kD protein mediates the binding of transforming growth factor-beta to cell surface and extracellular matrix proteoglycans. 833 95

Intravenous administration of sodium benzylideneascorbate (SBA) dose-dependently induced degeneration (vacuolar and eosinophilic degeneration and cell shrinkage and nuclear condensation, which are characteristic of apoptotic cell death) of 3'-methyl-4-dimethylaminoazobenzene-induced rat hepatocellular carcinoma. SBA did not significantly induce lymphocyte infiltration and fibrosis in the liver, nor damage the gross morphology of kidney and spleen cells. SBA failed to stimulate the production of tumor necrosis factor and interleukin-1 beta in both in vitro and in vivo systems. These results may suggest a direct antitumor action of SBA via induction of apoptosis in the tumor. However, SBA did not significantly affect the doubling time, or the extent of invasion and differentiation of dimethylhydrazine-induced colon carcinoma in rats. These data suggest that the conditions of SBA administration should be re-established for each tumor sample to produce maximum antitumor activity.
 ...
PMID:Effect of sodium benzylideneascorbate on chemically-induced tumors in rats. 838 96

Resistance modifying agents (RMA) such as verapamil (VER) have proved effective in reversing multidrug resistance (MDR) in many in vitro experimental models, but clinical results with RMA have been disappointing. To clarify this apparent discrepancy we have evaluated the cytotoxic effects of doxorubicin (DOX) plus VER in four human colon carcinoma (HCOC) cell lines (LoVo, DLD-1, SW948, SW1116). These lines were selected on the basis of their levels of mdr1 mRNA being similar to those expressed by HCC obtained from non-drug-treated patients. In all cell lines the sensitising effect of VER on DOX cytotoxicity was schedule-dependent and maximal potentiation of DOX cytotoxicity was obtained by exposure to VER for a time > or = the cells' population doubling time.
 ...
PMID:Increased chemosensitivity to doxorubicin of intrinsically multidrug-resistant human colon carcinoma cells by prolonged exposure to verapamil. 839 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>