Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of different phorbol esters and of mechanical treatment on the activity of ornithine decarboxylase in mouse epidermis in vivo was investigated. The strong promoter 12-O-tetradecanoylphorbol-13-acetate as well as the weak promoters phorbol dibenzoate and the 12-O-tetradecanoylphorbol-13-acetate analog 12-O-tetradeca-2-cis, 4-trans-6,8-tetraenoylphorobol-13-acetate strongly increased the activity of the enzyme and the intraepidermal level of putrescine, with a maximum at 5 hr after application, when applied in doses which evoke comparable proliferative and irritant responses in skin. The hyperplasiogenic but nonirritant and almost nonpromoting 4-O-methyl ether of 12-O-tetradecanoylphorbol-13-acetate did not show such effects. Mechanical removal of the uppermost horny layer led to a considerable increase of ornithine decarboxylase activity after 4 to 8 hr, while skin massage showed only a minute effect under conditions in which both treatments exhibit about the same mitogenic efficiency. Neither manipulation promotes tumor development. After skin massage, the induction of ornithine decarboxylase was influenced neither by treatments which alter the cyclic adenosine 3',5'-monophosphate level in epidermis (inhibition of phosphodiesterase, beta-adrenergic stimulation, and injection of dibutyryl cyclic adenosine 3',5'-monophosphate) nor by injection of epidermal G1 chalone. The results indicate that no clear-cut correlation exists between epithelial cell proliferation, development of hyperplasia, and tumor promotion on the one hand and an activation of epidermal ornithine decarboxylase on the other.
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PMID:Ornithine decarboxylase activity, cell proliferation, and tumor promotion in mouse epidermis in vivo. 22 17

Transplantable Brown-Pearce carcinoma was adapted successfully in the rabbit anterior chamber. Regression of tumor growth was attained on tri-weekly perfusion of the AC with 10 micromolar of methotrexate. Tumor cyclic nucleotide phosphodiesterase (PDE) and protein activator were found to be markedly depressed during the course of chemotherapy and the PDE cAMP/cGMP ratio was similarly altered. Corroborative light and electron-microscopic studies showed specific alterations of intracellular organelles in relation to MTX and tumor cell death. These findings suggest that metabolic pathways of cyclic nucleotides are important biochemical modulators of neoplastic cells. The method of intraocular perfusion precludes systemic toxic effects and avoids compromising the animals' immunocompetence.
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PMID:Experimental intraocular malignancy: the effect of intracameral perfusion. 23 85

The major ribonuclease of adult guinea pig epidermis has been isolated and purfied over 1000-fold by a combination of ammonium sulfate fractionation, affinity and ion-exchange chromatography, and electrophoresis. The purified enzyme is free from phosphodiesterase and phosphatase activities. The ribonuclease is optimally active near neutrality in phosphate buffer, with a Km of 3mu g/ml toward [14-C]RNA from Erhlich ascites tumor cells. (here are no metal requirements for activity. The enzyme catalyzes the endonucleolytic hydrolysis of high molecular weight yeast RNA and it also hydrolyzes polycytidylic and polyuridylic acids, but not polyadenylic, polyguanylic, and polyinosinic acids. The apparent molecular weight of the active enzyme is 28 500.
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PMID:Epidermal nucleases: purification and characterization of ribonuclease from mammalian epidermis. 23

ADP-Ribose is nearly quantitatively split to 5'-AMP by treatment with alkali at elevated temperatures. This unique behaviour, which is not shown by ADP and other adenine derivatives, was used as the basis of an optical test for the selective determination of ADPR in the presence of other adenine compounds including RNA. Poly(ADPR) could also be quantified when the polymer was degraded by poly(ADPR) glycohydrolase prior to alkaline treatment. When combined with the determination of the terminal AMP residues released by phosphodiesterase I treatment, the chain length of the polymer could be calculated. Application of the method to the quantitation of protein-bound mono(ADPR) residues in Ehrlich ascites tumor cells under different growth conditions is described.
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PMID:Conversion of ADP-ribose to 5'-AMP by alkaline treatment and its use for an optical quantitation of mono and poly(ADP-ribose) residues in the micromolar range. 55 24

Human papillary thyroid carcinoma (PTC) has a relatively benign prognosis despite a high frequency of lymphatic metastasis. This suggests that local anticancer factors, generated in lymph nodes, control PTC progression. The cytokine, tumor necrosis factor-alpha (TNF-alpha), may be one such factor. We have previously shown that a human PTC cell line (NP-PTC) has high affinity TNF-alpha receptors. We now report on the action of TNF-alpha in these cells. TNF-alpha decreased [3H]thymidine incorporation as well as cellular DNA content and cell number in a dose-dependent manner. The abundance of phosphodiesterase and manganous superoxide dismutase mRNA species was increased in a time- and dose-dependent manner in the NP-PTC cells after TNF-alpha treatment. TNF-alpha activated NF-kappa B, a nuclear factor thought to mediate multiple actions of TNF-alpha, in these cells with a maximum effect observed after 30 min of treatment. Thus, TNF-alpha has an antiproliferative action on NP-PTC cells, despite its ability to induce the accumulation of mRNA that encodes an enzyme (manganous superoxide dismutase), thought to be cytoprotective. The net antiproliferative effect must therefore be explained by a balance of protective and tumoricidal or static effects that ultimately result in control of tumor spread. These antiproliferative effects may be in part mediated by NF-kappa B and PDE.
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PMID:Tumor necrosis factor-alpha activates nuclear factor kappa B and induces manganous superoxide dismutase and phosphodiesterase mRNA in human papillary thyroid carcinoma cells. 132 6

In large part, malignancy is the end result of aberrant cell growth and differentiation. Control of these processes is anticipated to result in a suppression of oncogenicity. Retinoic acid (RA), a derivative of vitamin A, has been shown to inhibit proliferation, induce cell differentiation and reverse the malignant phenotype of a variety of tumor cell types. In order to further characterize the antitumor potential of RA, this study examined the in vitro and in vivo effects of this retinoid on cell lines derived from human neuroblastoma (NB). The in vitro phase of this study tested the ability of various compounds to raise intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels and either alone or in combination with RA, to promote differentiation of two relatively RA-resistant cell lines. Direct activation of the synthetic enzyme adenylate cyclase by forskolin or cholera toxin increased intracellular cAMP levels over 10-fold after 1 hour of treatment, declining over the next 16 to 24 hours. After 5 days of continuous growth in the presence of these agents, cAMP levels remained elevated 2- to 7-fold above control values and were accompanied by a decrease in cell proliferation and an increase in cell differentiation. All these effects were exaggerated in the presence of phosphodiesterase inhibitors. Isoproterenol and epinephrine did not alter cAMP levels and had no discernible biological effects. RA promoted differentiation with little effect on cAMP levels. Combination treatment of cells with RA plus agents that raised cAMP levels resulted in greater degrees of differentiation than seen with single-agent treatment. From these data, it was concluded that: 1. the cAMP synthetic and degradative pathways are functional in the NB cell lines studied; 2. elevation of cAMP is a sufficient but not necessary condition for inhibiting proliferation and promoting differentiation in these cells; 3. elevation of intracellular cAMP potentiates the differentiation-inducing activity of RA; and 4. overcoming retinoid resistance in some tumor cell lines may be feasible by alterations in the cAMP system. This would be of particular value in treating tumors that have lost retinoid responsiveness. The in vivo phase of this study examined the effects of single-agent treatment using RA on the development and growth in nude mice of tumors derived from a NB cell line.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effects of retinoic acid on the in vitro and in vivo growth of neuroblastoma cells. 132 87

The activity of a phosphodiesterase of the phospholipase C (PLC) type and factors influencing its activity were studied in ascites tumor cells. The enzyme confined to the 12,000 x g particulate fraction hydrolyses inositol phospholipids, with preference for phosphatidylinositol 4-phosphate (PtdIns(4)P) over phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), exhibiting maximum values of 61 and 15 nmol/min per mg protein, respectively, at a pH optimum of 5.5. The phosphodiesterase, which is strongly Ca2+ dependent with optimal free Ca2+ concentrations between 20 and 100 nM for both substrates, is almost completely inhibited (93-95%) in the presence of 2 mM EGTA. Only the PLC acting on PtdIns(4,5)P2 is significantly activated in the presence of 6-60 microM GTP gamma S. The low extent of enzymatic activity in the presence of 5 mM MgCl2 or chelating agents is suggestive of inositolphosphatase activity which is supported by the determination of small amounts of myo-inositol during HPLC analyses. Both dioleoylglycerol (DAG) and the membrane-permeable 1-oleoyl-2-acetyl-sn-glycerol (OAG) inhibit PLC activity, exhibiting IC50 values of 5 microM with PtdIns(4)P and approx. 10 microM with PtdIns(4,5)P2 as substrate and maximum inhibition up to 60% (DAG) and 80% (OAG). These data are indicative of a mechanism of direct negative feedback regulation of the enzyme by diglycerides which may explain the observed long-term effects of OAG on PLC activity in cell culture experiments.
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PMID:Ca2+ and partly GTP gamma S-dependent particulate phospholipase C hydrolyzing phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate is inhibited by diacyl(acyl-acetyl) glycerols. 133 19

Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders. The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells. Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-1 beta, or 5 ng/ml tumor necrosis factor-alpha for 4 hours led to increased tissue factor procoagulant activity. Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents. Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor. An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were 100 times less potent. Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry. Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP. This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase. The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP. These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.
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PMID:Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism. 137 7

Cartilage breakdown, as seen in inflammatory and degenerative joint diseases, can be mediated by proteolytic enzymes, such as the metalloproteinase collagenase, the only enzyme able to digest collagen at neutral pH. In vitro collagenase gene expression can be stimulated by the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. We have investigated the effect of prostaglandin E1 (PGE1) on 12-O-tetradecanoyl-phorbol-13-acetate-stimulated collagenase mRNA levels in the rabbit synoviocyte cell line HIG-82. PGE1, but not PGE2 or PGF2 alpha, was able to selectively reduce collagenase mRNA levels in a dose-dependent fashion. PGE1 markedly increased intracellular levels of cAMP, while PGE2 and PGF2 alpha had little or no effect on cAMP production in the HIG-82 synoviocytes. Agents known to increase intracellular cAMP levels, such as the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), mimicked the effect of PGE1, on collagenase mRNA levels. PGE1, forskolin, and IBMX also decreased collagenase mRNA levels in human skin fibroblasts, demonstrating that this observation was not unique to the HIG-82 cell line. Transient transfection experiments carried out in HIG-82 cells using a 1.2-kilobase portion of the 5'-flanking region of the human collagenase gene linked to the reporter gene luciferase demonstrated that PGE1, forskolin, and IBMX exert their inhibitory effect on the promoter region of the collagenase gene.
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PMID:Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts. 137 21

The rat insulinoma RIN 5F and the mouse pituitary AtT-20 cell line, which are known to express several biologically active peptides, were found to express CCK mRNA, to correctly process, and to release immunoreactive cholecystokinin (CCK) peptides. They expressed low levels of these peptides (about 0.4 and 0.2 ng/mg protein, respectively) and both cell lines processed pro-CCK to a form which co-eluted with CCK 8 sulfate on Sephadex gel filtration chromatography and HPLC. The major CCK 8 immunoreactive peptide which they secreted co-eluted with CCK 8 on Sephadex G-50 chromatography. The secretion of CCK from both cell lines was significantly enhanced by treatment for 24 h with forskolin + IBMX (3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor). This treatment also doubled the CCK content of the AtT-20 cells. It appears that the ability of different endocrine tumor cells to express and process CCK is not as uncommon as previously thought. These cells should be useful for future studies of CCK expression, processing, and regulation of secretion.
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PMID:CCK mRNA expression, pro-CCK processing, and regulated secretion of immunoreactive CCK peptides by rat insulinoma (RIN 5F) and mouse pituitary tumor (AtT-20) cells in culture. 138 Jun 77


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