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)

In FRSK cells, a cell line derived from fetal rat epidermal cells, cyclic AMP-elevating agents forskolin (10 microM) and cholera toxin (10 ng/ml) increased cellular cyclic AMP content and suppressed [3H] thymidine incorporation. These effects of forskolin were enhanced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1 mM). Dibutyryl cyclic AMP (1 mM), an analog of cyclic AMP, decreased not only basal but also both tumor promoter 12-O-tetradecanoylphorbol-13-acetate- and epidermal growth factor-stimulated [3H] thymidine incorporation. From these results, we suggest that cyclic AMP may be a negative regulatory factor of DNA synthesis in FRSK cells.
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PMID:Cyclic AMP as a negative regulator of DNA synthesis in FRSK cells, a fetal rat epidermal cell line. 247 Jul 96

We have previously reported that many tumor cell lines express a 5'-nucleotide phosphodiesterase (phosphodiesterase I, EC 3.1.4.1) with properties clearly distinguishable from enzymes of normal tissues (Biochim. Biophys. Acta (1988) 966, 99-106). Such an enzyme with 5'-nucleotide phosphodiesterase activity was purified from Ehrlich ascites carcinoma by measuring the cleavage of thymidine 5'-monophosphate p-nitrophenyl ester (TMP-NP). The enzyme is a soluble protein, has a pH optimum of 7.5, and the molecular mass estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis is 67 kDa. The enzyme does not hydrolyze other chromogenic substrates for phosphodiesterases, nor pyrophosphate bond of various nucleotides which are cleaved by 5'-nucleotide phosphodiesterases of normal tissues. But, it hydrolyzes dinucleotides to form 5'-phosphates, and is more active on 2',5'- than on 3',5'-phosphodiester bonds. These results indicate that the TMP-NP splitting enzyme in Ehrlich ascites carcinoma cells is a 2',5'-phosphodiesterase.
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PMID:A nucleotide phosphodiesterase with preference for 2',5'-phosphodiester bonds from Ehrlich ascites carcinoma. 254 94

We have previously reported that treatment of hen granulosa cells with the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), or the diacylglycerol analog, 1-oleoyl-2-acetylglycerol (OAG), attenuates the steroidogenic response to luteinizing hormone (LH) at sites both prior and distal to the formation of cyclic 3',5'-adenosine monophosphate (cAMP). The present study was designed to determine the site(s) of inhibition within the steroidogenic pathway by evaluating the effects of OAG and PMA on key enzyme systems involved in hen granulosa cell steroidogenesis: adenylyl cyclase, phosphodiesterase, the cholesterol-side-chain-cleavage (CSCC) complex and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). The adenylyl cyclase activator, forskolin (0.1 mM), stimulated a 3.3-fold increase in granulosa cell cAMP formation, and this increase was inhibited by the presence of OAG (2.5, 25 and 63 microM) in a dose-dependent manner. By contrast, a 1.8-fold increase in cAMP accumulation induced by the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX; 1.0 mM), was not altered by OAG at any dose (2.5, 25 and 63 microM). Inclusion of 25-hydroxycholesterol (2500 ng/tube) in the incubation medium in the presence of 1.0 microM cyanoketone resulted in a 10-fold increase in pregnenolone production. Increasing concentrations of OAG (2.5, 25 and 63 microM) caused a dose-dependent suppression of the conversion of 25-hydroxycholesterol to pregnenolone. On the other hand, granulosa cells incubated with 200 ng/tube pregnenolone increased progesterone production 100-fold, but this increase was not inhibited by either PMA (3.2, 32, 8.1 and 162 nM) or OAG (2.5, 25 and 63 microM). The results indicate that activation of protein kinase C can suppress the function of at least two key enzymes involved in hen granulosa cell steroidogenesis. Inhibition of adenylyl cyclase greatly reduces the steroidogenic response of granulosa cells to endocrine factors that act via increasing levels of cAMP (i.e. LH). Furthermore, a reduction in CSCC activity limits the availability of precursor required for progesterone production. These data provide additional evidence of a role for protein kinase C in modulating ovarian function in the domestic hen.
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PMID:Mechanisms by which a phorbol ester and a diacylglycerol analog inhibit hen granulosa cell steroidogenesis. 254 39

Recent data from many laboratories suggest that insulin stimulates diacylglycerol formation. Data presented in this manuscript demonstrate an insulin-like effect of PMA, a tumor promoting agent that mimics the action of diacylglycerol, in isolated adipocytes on; (a) glucose oxidation using uniformly labelled, C-1-labelled and C-6-labelled glucose, (b) epinephrine-induced lipolysis and (c) low Km cAMP phosphodiesterase activity. Additionally, a lipolytic effect of PMA is identified when unopposed by epinephrine. These data not only demonstrate an insulin-like effect of phorbol esters in adipose tissue but they lend support to the concept of diacylglycerol involvement in the mechanism of insulin action.
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PMID:The insulin-like effects of phorbol myristate acetate (PMA) in the isolated fat cell. 254 2

We have investigated control mechanisms of TNF receptor expression (TNF-R) in various human tumor cells and normal peripheral blood monocytes. Activators of protein kinase A (PKA) signal transduction pathways were found to enhance TNF-R expression up to sevenfold, whereas in the same cells, IFN-alpha and -gamma receptors remained unaffected. Inhibitors of protein kinases downregulate both constitutive and cAMP-enhanced TNF-R expression. Binding studies revealed an increase in TNF-R numbers without a change in receptor affinity. Both, direct activators of PKA and inhibitors of phosphodiesterase, raising intracellular levels of cAMP, were found to be effective. As activation of PKA does not slow down the degradation rate of TNF-Rs, but rather enhances protein synthesis-dependent reexpression of TNF-Rs after transient PKC-mediated transmodulation and after tryptic digestion of TNF-Rs, it is concluded that PKA stimulates TNF-R synthesis. Maximum TNF-Rs enhancement is reached after 24 h of stimulation and is reversible, suggesting that receptor upregulation is not linked to irreversible steps of cellular differentiation. PKA-mediated enhancement of TNF-R expression was predominantly observed in normal peripheral blood monocytes and tumor cell lines of myeloid origin. As in these typical TNF producer cells, the production of TNF is also controlled by PKA and PKC, a regulatory circuit is proposed, by which these two independent signal pathways antagonistically regulate TNF production and, at the receptor level, TNF sensitivity.
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PMID:Antagonistic control of tumor necrosis factor receptors by protein kinases A and C. Enhancement of TNF receptor synthesis by protein kinase A and transmodulation of receptors by protein kinase C. 254 68

1-Oleoyl-2-acetyl-sn-glycerol (OAG), the membrane-permeable analogue of 1,2-diacylglycerol (DAG), which stimulates ascites tumor cell proliferation, was used to study its effect on phosphoinositide metabolism. Culturing of ascites cells labeled with [3H]inositol at low serum concentration in the presence of OAG suppressed the radioactivity level of the inositol phosphates, particularly IP3. Membrane-bound, Ca(2+)- and GTP gamma S-sensitive PI- and PIP2-specific phosphodiesterase (phospholipase C) showed much lower activities in OAG-stimulated cells, which could be enhanced by GTP gamma S in these but not in the unstimulated cells. A high susceptibility to Ca2+ of the PI- and PIP2-specific phospholipase C of non-stimulated cells was observed. The PIP-kinase activity was similarly reduced by about 85% in OAG-stimulated cells. These data indicate a negative feedback regulation of the phosphoinositide metabolism mediated by OAG. Reduction in synthesis and degradation of PIP2, which furnishes the two second messengers, DAG and IP3, provides a means of controlling the intracellular level of these molecules, which is important for a balanced proliferation rate.
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PMID:Effect of 1-oleoyl-2-acetyl-sn-glycerol on inositol lipid metabolism of ascites tumor cells in culture. 256 33

Peri-tumoral injection of recombinant human interleukin-1 beta in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3Cl-8) with IL-1 beta barely inhibited cell multiplication. IL-1 beta, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL-1 beta of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL-1 injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF-alpha or beta. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within 1 hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri-tumoral injection of IL-1 beta or TNF-beta. After 6 hr, both cytokines induced a 3-fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophosphorylethanolamine, an accumulation of sn-glycerol 3-phosphate and a more than 10-fold increase in the choline/phosphorylcholine ratio. These results are similar to those reported for TNF-alpha, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 3.1.4.2) and partial inhibition of choline kinase (EC 2.7.1.32). IL-1 beta and TNF-beta (like TNF-alpha) also induced alkaline shifts (0.10-0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL-1 beta or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.
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PMID:Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta. 278 94

Rat C 6 glioma is known to possess a beta-adrenergic receptor with which intracellular cyclic adenosine monophosphate (cAMP) levels are altered to control cell growth in vitro. In order to study the effect of beta-adrenergic agonist, isoproterenol, in growth-inhibitory action upon C 6 glioma cells, subcutaneous tumor models and meningeal gliomatisis (MG) models as a brain tumor model have been exposed to the treatment of isoproterenol. Growth of subcutaneous tumor was suppressed by the treatment of the drug, and the survival time of MG rats was prolonged by the intrathecal (i. t.) injection of isoproterenol. The addition of papaverine, phosphodiesterase inhibitor, to the treatment schedule augmented the growth-inhibitory effect of isoproterenol. Therefore, it is concluded that the survival time of the brain tumor models could be prolonged through the inhibition of the growth of C 6 glioma cells by such drugs as those which elevate intracellular cAMP levels.
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PMID:[Treatment of rat glioma with a beta-adrenergic agonist and a phosphodiesterase inhibitor in vivo]. 282 9

Y1 adrenal tumor cells are resistant to the steroidogenic effect of A-II though they possess specific A-II binding sites. The number of these binding sites is lower in Y1 cells than in bovine adrenal cells, but the affinity is similar in the two models. Moreover, Y1 cells are shown to contain a high level of cytosolic protein kinase C whose properties appear similar to those observed in bovine adrenal cells. However, the activation of protein kinase C by a phorbol ester (PMA) or diacylglycerol (OAG) does not induce steroidogenesis in Y1 cells. On the other hand, A-II, without any effect on adenylate cyclase in basal conditions, reduces the ACTH-induced cAMP production in Y1 cells. This inhibitory effect of A-II is not blocked by phosphodiesterase inhibitor but is completely abolished after 24 hours of pretreatment of intact cells with pertussis toxin. This inhibition is probably mediated by the inhibitory guanine nucleotide regulatory protein (Gi) since the labeled 41 KD-ADP ribosylated protein disappeared after 24 hours of pretreatment of intact cells with pertussis toxin. Moreover, the accumulation of inositol phosphates under A-II stimulation was low, which suggests that the coupling of A-II receptors with phospholipase C is reduced in Y1 cells. The Y1 cell line is probably a good model to study the post membrane events in A-II action.
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PMID:Angiotensin II (A-II) steroidogenic refractoriness in Y-1 cells in the presence of A-II receptors negatively coupled to adenylate cyclase. 282 18

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.
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PMID:Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188. 283 Apr 7


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