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)

T cells expressing high levels of the T cell receptor (TCRhigh) differentiate in the major intrathymic pathway and then distribute to the peripheral immune organs, whereas T cells expressing intermediate levels of the TCR (TCRint) differentiate in both extrathymic pathways and an alternative intrathymic pathway and localize in unique sites, including the liver and thymic medulla. Since TCRint cells constitutively express interleukin-2 receptor beta-chain (IL-2R beta), two-color staining for CD3 (or TCR) and IL-2R beta clearly distinguished IL-2R beta+ CD3int (or TCRint) cells from IL-2R beta-, CD3high cells. CD3int cells may be considered to be primordial T cells based on their phenotype, morphology and other functional properties. In this study, using anti-V beta mAb in conjunction with the endogenous superantigen Mls, the distribution of self-reactive clones among T cells generated in all of the above pathways was investigated in mice. Self-reactive T cell clones were confined to IL-2R beta+, CD3int cells, in all of the organs tested. A significant proportion of self-reactive clones was never identified among CD3high cells in the thymus and peripheral immune organs in either young (8 week old) or old (50 week old) mice. Possibly reflecting their self-reactivity, CD3int cells, but neither NK cells nor CD3high cells had a potent cytotoxic effect against a syngeneic hepatoma in the presence of anti-CD3 mAb. These results raise the possibility that CD3int cells seen in the liver and thymus might belong to a similar primordial lineage of T cells, and that self-reactive clones are not generated through the major intrathymic pathway, but only through extrathymic pathways and an alternative intrathymic pathway.
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PMID:Self-reactive T cell clones in a restricted population of interleukin-2 receptor beta+ cells expressing intermediate levels of the T cell receptor in the liver and other immune organs. 766 91

To investigate whether DNA replication in malignant cells deviates from that of normal cells we compared DNA polymerases alpha, delta, and epsilon from normal rat liver to the enzymes from fast-growing (malignant) Novikoff hepatoma cells. DNA polymerases were purified 300-fold by three chromatographic steps. Characterization included measurement of physicochemical constants (including sedimentation coefficients, diffusion coefficients, calculation of relative molecular masses), quantitation of catalytic activities using specific DNA primer templates (Km values) and inhibitors (Ki values), and identification of polypeptides which are strongly associated with DNA polymerases. Comparison of physicochemical and catalytic properties of DNA polymerases from both sources revealed similarities but also some important differences. DNA primase associated with DNA polymerase alpha, and 3'-5' exonuclease accompanying DNA polymerases delta and epsilon had similar activities. In contrast, the DNA-binding domain of DNA polymerases alpha and epsilon from hepatoma cells was altered since Km values, determined with the specific primer templates gapped calf thymus DNA and poly(dA.dT), were higher. Furthermore, sedimentation and diffusion coefficients, Stokes' radii, and frictional coefficient ratios of DNA polymerases alpha and epsilon from malignant cells significantly deviated. In addition, when the dNTP-binding sites were probed with specific inhibitors (aphidicolin, butylphenyl-dGTP, carbonyldiphosphonate, and dideoxy-TTP), significantly lower Ki values were obtained for the polymerases from Novikoff cells indicating lower affinity of the dNTP binding site to deoxyribonucleoside 5'-triphosphates. Altered catalytic and molecular properties are possibly a consequence of malignant transformation. It is to be expected that similar changes occur in DNA polymerases of other tumors. In particular, diminished affinity to primer templates and weakened nucleotide binding leads to lowered specificity of nucleotide selection in the base-pairing process and is therefore likely to cause an enhanced mutation rate during malignant progression.
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PMID:DNA polymerases alpha, delta, and epsilon of Novikoff hepatoma cells differ from those of normal rat liver in physicochemical and catalytic properties. 767 Sep 30

Two cDNA clones representing rat hepatoma thymidylate synthase (rTS) were isolated from a lambda ZAP II cDNA library using as a probe a fragment of the human TS cDNA. The two were identical except that one was missing 50 bp and the other 23 bp corresponding to the 5' coding region of the protein. The missing region was obtained by screening a rat genomic library. The open reading frame of rTS cDNA encoded 921 bp encompassing a protein of 307 amino acids with a calculated molecular mass of 35,015 Da. Rat hepatoma TS appears identical to normal rat thymus TS and the two sequences differ from mouse TS in the same eight amino acid residues. Six of these differences are in the first 21 amino acids from the amino-end. The human enzyme differed from rat and mouse TS at 17 residues where the latter two were identical, with most changes being conservative in nature. The three species differed completely at only four sites. Because the mouse TS shares four amino acids with human TS at sites which differ from rTS and a comparable situation does not exist between rTS and human TS, it is suggested that mouse TS is closer to human TS phylogenetically than rTS. The polymerase chain reaction was used to subclone the protein coding region of rTS into a high expression vector, which expressed rTS in Escherichia coli to the extent of 10 to 20% of its cellular protein. Although the amino-end of the amplified TS was unblocked, that isolated from a FUdR-resistant rat hepatoma cell line contained mostly N-acetylmethionine on its N-terminal end, a finding that may have significant regulatory consequences, which are discussed. The TS level in the resistant cell line was 60 to 70-fold higher than normal which was found to be associated with both multiple gene copies and an expanded TS mRNA pool.
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PMID:Isolation and expression of rat thymidylate synthase cDNA: phylogenetic comparison with human and mouse thymidylate synthases. 771 Oct 67

Transferrin (Tf) plays an important role during immunologic activation by donating iron to activated lymphocytes. Therefore, synthesis by lymphomyeloid cells has been investigated. Mouse macrophages and macrophage cell lines synthesized Tf, with levels being markedly increased by gamma-interferon (gamma-IFN) and, to a lesser extent, by interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF alpha). Tf was also produced by phytohemagglutinin-stimulated human T cells and two T-cell lines and was increased by IL-2. Even after appropriate activation, none was synthesized by human macrophages or monocytic cell lines or by mouse T cells, T-cell lines, or thymus cells. In both species, B-lineage cell lines were negative. Tf was also synthesised by macrophages from congenitally hypotransferrinemic mice and was responsive to gamma-IFN, but levels were lower than those from normal controls. Synthesis by human and murine hepatoma cells was increased by IL-6 but unaffected by IL-1, TNF alpha, or gamma-IFN. Iron decreased synthesis by hepatoma cells but had no effect on the lymphomyeloid cells. Tf mRNA levels paralleled protein synthesis, suggesting that regulation was pre-translational. Thus, Tf synthesis by lymphomyeloid cells is regulated differently from hepatic synthesis, which is consistent with the suggestion that Tf may act in a paracrine (mouse) or autocrine (human) manner on activated lymphocytes.
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PMID:Cytokine-mediated regulation of transferrin synthesis in mouse macrophages and human T lymphocytes. 784 92

In an effort to test the hypothesis that 9 alpha-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog, 10, of methyl 11 beta, 21-dihydroxy- 3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay, 10 was found to be twice as potent as 1. This increase in topical potency was consistent with enhanced binding affinity of 10, relative to 1. The IC50 values for displacement of [3H]dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 microM for 10, 1, and prednisolone, respectively. Following multiple topical ID50 applications of predniosolone, 1, and its new fluorinated analog, 10, in the rat subacute croton oil-induced ear edema bioassay, only prednisolone exhibited significant untoward effects, such as reduction in relative thymus and adrenal weights, plasma corticosterone levels, and normal body weight gain. Thus, while fluroination of 1 enhanced its topical potency, there was not a concomitant increase in untoward systemic effects. This lack of adverse systemic effects is ostensibly due to the presence of the metabolically labile 16-carboxylate ester moiety.
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PMID:Novel fluorinated antiinflammatory steroid with reduced side effects: methyl 9 alpha-fluoroprednisolone-16-carboxylate. 791 64

The activity of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase; EC 2.7.1.68), the second ATP-utilizing enzyme of 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in the rat in a spectrum of transplantable solid hepatomas of different growth rates and in normal tissues of high and low cell renewal rates. In a standard isotopic method developed for the assay, the enzyme activity was linear with time for 4 min and proportional with protein concentration over a range of 0.05 to 1 mg per 0.135-ml reaction mixture. The apparent Km for the substrate PIP (phosphatidylinositol 4-phosphate) and for ATP and Mg2+ in normal liver were 0.06, 0.5, and 4.2 mM, respectively, and in rapidly growing hepatoma 3924A, 0.08, 0.7, and 7.1 mM. The kinase activity in adult Wistar rat liver was 0.046 +/- 0.003 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, PIP kinase activity increased 3.3-9.7-fold, and in hepatoma 3924A, it was elevated 45-fold over that of normal liver. When hepatoma 3924A cells were plated and expressed their proliferative program, enzyme activity increased 4.3-fold in mid-log phase. To further clarify the linkage between PIP kinase activity and proliferation, enzyme activity was determined in rat organs of high and low cell renewal capacity. The PIP kinase activity in rat thymus, bone marrow, spleen, and testes was 5.4-, 6.3-, 4.8- and 4.3-fold higher, respectively, than in normal rat liver; in lung, brain, skeletal muscle, renal cortex, and heart, the activities were low. In all tissues examined, the activity of PIP kinase was 4.6 to 18% of that of phosphatidylinositol kinase. Since enzymes of crucial significance frequently have short half-lives, the decay rates of PIP kinase were examined in liver, bone marrow, and hepatoma 3924A in rats injected with cycloheximide, which inhibits protein biosynthesis. In cycloheximide-treated animals, PIP kinase had the shortest decay rate (t1/2 = 0.12 h) in comparison with eight enzymes of purine and pyrimidine biosynthesis of rat bone marrow (t1/2 = 0.6 to 4.3 h). In liver and solid hepatoma 3924A, the activity of PIP kinase was degraded less rapidly (t1/2 = 5 h). The relationship of PIP kinase activity with proliferation and transformation is apparent in the high activity in thymus, bone marrow, spleen, and testes and in the increased activities in the rat hepatomas of different growth rates. The coordinate increases in phosphatidylinositol and PIP kinase activities suggest that the capacity for signal transduction is heightened in cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): a proliferation- and malignancy-linked signal transduction enzyme. 792 99

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.
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PMID:In vitro formation of DNA adducts with bile acids. 792 85

5-Aminolevulinic acid (ALA), a heme precursor accumulated in chemical and inborn porphyrias, may behave as an endogenous pro-oxidant. In chronically treated rats (40 mg ALA/kg body wt every 2 days for 15 days) the steady-state level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in liver DNA (94.5 +/- 23.3 residues/10(6) dG) was 4.5 times higher than in non-treated rats (21 +/- 7.5 residues/10(6) dG). In vitro exposure of calf thymus DNA to ALA (0.05-5 mM) in the presence of 10 microM Fe2+ caused the formation of 8-OHdG. The amount of 8-OHdG rose from 135 +/- 15 residues/10(6) dG in the control system to 1140 +/- 150 residues/10(6) dG after incubation with 5 mM ALA and 10 microM Fe2+. Diethylenetriaminepentaacetic acid (5 mM) or mannitol (100 mM) inhibited the formation of 8-OHdG by 63 and 69% respectively, evidencing the involvement of both H2O2 and HO. in this process. Hydrogen peroxide (100 microM) or Fe2+ alone did not cause DNA oxidation. The present data support the hypothesis that ALA-generated reactive oxygen species can oxidize DNA and may be involved in the development of primary liver cell carcinoma in individuals with symptomatic acute intermittent porphyria.
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PMID:5-Aminolevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2'-deoxyguanosine in DNA. 795 60

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.
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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

The activity of 1-phosphatidylinositol 4-kinase (EC 2.7.1.67), the first committed ATP-utilizing enzyme of inositol 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in a spectrum of rat hepatomas of different growth rates, in sarcoma, and in normal tissues of high cell renewal rates which include differentiating and regenerating liver. A standard isotopic method was developed to measure the enzymic activity in crude particulate extracts. In this assay, the enzyme activity was linear with time for 2 min and proportional with protein concentrations over a range of 0.1 to 1.0 mg per 0.1 ml reaction mixture. The optimum pH for both liver and hepatoma enzyme was 7.4. The apparent Km values of the kinase for ATP, Mg2+, and the substrate phosphatidylinositol in normal liver were 0.03, 10, and 0.2 mM, respectively, and in rapidly growing hepatoma 3924A 0.01, 0.1, and 5.3 mM. The kinase activity in adult rat livers was 0.3 to 0.5 +/- 0.01 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, kinase activity increased 5.3- to 7.6-fold, and in rapidly proliferating hepatoma 3924A, it was elevated 28.5-fold over that of normal liver. In rat sarcoma, kinase activity was 13.2-fold higher than in normal muscle. To clarify further the linkage between kinase activity and proliferation, enzymic activity was determined in rapidly growing rat tissues. The kinase activity in rat thymus, bone marrow, spleen, and testis increased 8.4-, 7.6-, 5.6- and 5.6-fold, respectively, over the values of normal rat liver; by contrast, in skeletal muscle, liver, heart, and renal cortex, the activities were low. In the rapidly growing neonatal rat liver and in 24-h regenerating liver, activities were 3.4- and 3.0-fold higher than in the adult resting liver. From this study, the relationship of 1-phosphatidylinositol 4-kinase activity with transformation and cell proliferation is clearly apparent in the markedly increased activity in transplantable hepatomas of different growth rates and in sarcoma and is further emphasized by the high activity observed in newborn and regenerating liver and in thymus, bone marrow, spleen, and testis. Since the kinase activity is linked with proliferation and malignancy, it may well be a sensitive target for chemotherapy.
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PMID:1-Phosphatidylinositol 4-kinase: an enzyme linked with proliferation and malignancy. 816 87


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