Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of cyclic adenosine 3:5-monophosphate (cyclic AMP) phosphodiesterase activity in homogenates of malignant and cyclic AMP-induced "differentiated" neuroblastoma cells was studied. Neuroblastoma cells of at least three mouse and one human clone had both the low (2 to 4 muM) and the high (66 to 106 muM) Km phosphodiesterase. In cyclic AMP-induced differentiated cells the values of Km were decreased, whereas the values of Vmax appeared to be slightly increased. Magnesium and manganese stimulated phosphodiesterase activity. Calcium, zinc, copper, mercury, ethylenediaminetetraacetic acid, and imidazole completely inhibited phosphodiesterase activity in malignant cells, whereas the above agents, except ethylenediaminetetraacetic acid, only partially inhibited enzyme activity in differentiated cells. Ethylenediaminetetraacetic acid completely reduced phosphodiesterase activity in differentiated cells. The pH optimum for phosphodiesterase activity was about 8 in both malignant and differentiated cells. The present studies show that the values of Km and Vmax and the sensitivity of phosphodiesterase activity to divalent ions change in cyclic AMP-induced differentiated neuroblastoma cells, and therefore we propose that the reverse may be true during malignant transformation of nerve cells.
Cancer Res 1975 Jan
PMID:Cyclic adenosine 3':5'-monophosphate phosphodiesterase activity in malignant and cyclic adenosine 3':5'-monophosphate-induced "differentiated" neuroblastoma cells. 23 30

The inhibitors of cyclic AMP phosphodiesterase (papaverine and 4-(-3-butoxy-4-methoxybenzyl)-2-imidazolidinone), serum-free medium, and x irradiation caused cell death and neurite formation in human neuroblastoma cells in culture (IMR-32), whereas theophylline was ineffective. Prostaglandin (PG) E1, N6O'2-dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) induced neurites without causing cell lethality. Inhibitors of phosphodiesterase and PGE1 increased the intracellular level of cAMP by about 2- and 4-fold respectively, whereas serum-free medium and x irradiation did not. The combination of PGE1 and phosphodiesterase inhibitor was more effective in causing morphological differentiation and in increasing the cAMP level than the individual agent. Sodium butyrate induced cell death and neurites, probably in part by increasing the cAMP level. cAMP, guanosine 3',5'-cyclic monophosphate, and adenosine had no detectable effect on the growth or morphology of neuroblastoma cells in culture. Adenosine 5'-monophosphate produced cell death without causing neurite formation. DbcAMP, and to a much lesser degree, sodium butyrate increased the tyrosine hydroxylase activity.
Cancer 1975 Oct
PMID:Role of cyclic AMP in differentiation of human neuroblastoma cells in culture. 24 May 3

The growth of a 3-methylcholanthrene-induced fibrosarcoma of C3H mice was inhibited by aspirin and indomethacin. While the tumour contained relatively high concentrations of PGE2-like material, that were markedly diminished by indomethacin treatment, our results did not confirm the recently proposed hypothesis that the anti-tumour effect arises from a restoration of depressed immune function. For example, mice that had completely eliminated their tumours under indomethacin administration were not immune to rechallenge. The tumour-bearing animals were not non-specifically immunodepressed, as their splenic PFC responses against SRBC were enhanced. However, while indomethacin augmented the PFC response in normal mice, this adjuvant effect was depressed in tumour-bearing animals. The spleen-cell PHA responses of tumour bearers were severely depressed, and such cells suppressed the PHA response of normal cells. Only after prolonged indomethacin treatment did animals (with comparable tumour burdens) show weak PHA responses and somewhat diminished suppressive activity. Possible alternative mechanisms, such as direct cytotoxicity, or inhibition of inflammation, phosphodiesterase activity, blood coagulation or calcium availability were not implicated (nor definitively excluded) in the anti-tumour effect.
Br J Cancer 1978 Oct
PMID:Mechanism of inhibition of tumour growth by aspirin and indomethacin. 36 11

Out of 17 enzymes studied, only 9 were detectable by starch gel electrophoresis in mouse neuroblastoma cells in culture. Prostaglandin E1 (PGE1) and 4(-3-butoxy-4-methoxybenzyl)-2-imidazolidinone (R020-1724), a specific inhibitor of cAMP phosphodiesterase, were used to induce "differentiation". Lactate and 6-phosphogluconate dehydrogenases and adenylate kinase were expressed as single bands in untreated neuroblastoma and induced "differentiated" cells, but the electrophoretic mobility of these enzymes in PGE1-treated cells was slower than that in malignant and R020-1724-treated cells. Three bands of glucose 6-phosphate dehydrogenase were detectable in PGE1-treated cells, whereas the R020-1724-treated cells had two bands and the untreated neuroblastoma cells had only one band. Aldolase was also expressed as a single band; however, the activity of this enzyme was much higher in PGE1-treated cells, whereas the activity was bately detectable for R020-1724-treated and untreated neuroblastoma cells. Some of the enzymes which are present in vivo are absent in vitro. Alkaline phosphatase is present in brain but is absent in neuroblastoma cells in vivo and in vitro. Two bands each of triose phsophate isomerase, fumarase and aldolase are present in brain, but only one band of these enzymes is present in neuroblastoma cells. Although PGE1 and R020-1724 induce many differentiated functions in neuroblastoma cells in a similar manner, PGE1 appears to change characteristically the expression of several enzymes.
Br J Cancer 1976 Sep
PMID:Altered enzyme expression in "differentiated" murine neuroblastoma cells. 97 99

In cytological investigations the following forms of cancer of the prostate may be verified: differentiated (clear-cellular and dark-cellular adenocarcinoma); poorly differentiated; and nondifferentiated (microcellular and polymorphic-cellular cancer). In the unchanged epithelium of the prostate there was noted a high activity of acid phosphotase, nonspecific esterase, nonspecific 5'-exonuclease, acid RNA-ase, acid DNA-ase, leucine aminopeptidase, and the absence of activity of alkaline phosphotase, neutral DNA-ase, alkaline RNA-ase. In the cancerous epithelium the activity of leucine aminopeptidase was either drastically decreased or absent altogether; the activity of acid DNA-ase and acid RNA-ase was non-uniform with the tendency to decrease in poorly differentiated tumours. The activity of other investigated enzymes in the cancerous epithelium showed no significant changes. At early stages of development of squamous cell metaplasia in the epithelium there was identified alkaline RNA-ase dissapearing in manifested metaplastic changes.
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PMID:[Cytology and enzymocytochemistry of nodose hyperplasia and cancer of the prostate]. 102 Oct 55

Polyinosinic with polycytidylic acid (poly l with poly C), a double-stranded synthetic RNA, produced in newborn rats a runt syndrome characterized by mortality and retarded growth rates of the total body, thymus, and kidneys. In contrast, it induced a hyperplasia in the epidermis and in the spleen. Within 10 days of treatment, the epidermis became 2 or 3 times thicker and the spleen mass was increased by 50%. The epidermal hyperplasia involved all layers, but hair follicles were excluded. Splenic hyperplasia did not result from accelerated erythropoiesis. Double-stranded RNA was required; single-stranded homopolymers were ineffective. Theophylline, a phosphodiesterase inhibitor, did not potentiate the effects. The uptake of iododeoxyuridine-125 was not enhanced in the hyperplastic epidermis or spleen. Thus we concluded that poly l with poly C can retard the growth of some organs in newborn rats, but that it causes epidermis and spleen to accumulate cells. The cytokinetic mechanisms involved in these contrasting effects were not clear.
J Natl Cancer Inst 1975 Jan
PMID:Runt syndrome induced in the rat by polyinosinic-polycytidylic acid. 107 99

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 rationale for melanoma-specific antitumor agents containing phenolic amines is based in part on the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. The phenolic amine compounds 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) inhibited in situ thymidylate synthase activity in pigmented melanoma cell lines but had little or no effect on nonpigmented and nonmelanoma cell lines. Theophylline, a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, increased tyrosinase activity and potentiated the inhibition of in situ thymidylate synthase by N-Ac-4-S-CAP. The inhibition of in situ thymidylate synthase by both drugs in pigmented melanoma cells correlated with the inhibition of DNA synthesis and cell growth and was not due to an indirect effect caused by inhibition of the enzyme dihydrofolate reductase. 4-S-CAP inhibition of thymidylate synthase activity in cell free extracts required oxidation of the drug. In the presence of tyrosinase, the concentration causing a 50% inhibition of thymidylate synthase activity (IC50) in cell-free extracts was less than 10 microM, but no inhibition was observed in its absence, even at a drug concentration of 500 microM. Two reducing agents, dithioerythritol and glutathione, effectively blocked the inhibition of thymidylate synthase by oxidized 4-S-CAP. In pigmented melanoma cells containing the enzyme tyrosinase, the quinone-mediated mechanism of inhibition of DNA synthesis via inhibition of thymidylate synthase may be uniquely important in the expression of phenolic amine cytotoxicity.
Cancer Chemother Pharmacol 1992
PMID:Thymidylate synthase as a target enzyme for the melanoma-specific toxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol. 150 78

The clinical usefulness of serum 5'-nucleotide phosphodiesterase isozyme-V (5'-NPD-V) assay as a serological marker for hepatocellular carcinoma was evaluated. Serum levels of 5'-NPD-V were measured by polyacrylamide gel electrophoresis in 536 Japanese patients with various diseases, including 120 patients with hepatocellular carcinoma. Icteric serum was not an indicator for the measurement of this isozyme, because jaundice gave a non-specific false-positive reaction. In 99 cases of hepatocellular carcinoma without jaundice, 73 (74%) had positive 5'-NPD-V and 24 (24%) showed levels greater than (+ +). The diagnostic value of this isozyme for hepatocellular carcinoma was relatively high, especially in patients with low or negative AFP levels. Diagnostic application for serum 5'-NPD-V assay to small liver tumors was limited. 5'-NPD-V showed false-positive results even in certain cases of benign liver diseases such as chronic hepatitis and liver cirrhosis, but cases with positivities stronger than (+ +) were few. Moreover, the test might be useful for the prediction of liver metastasis in cancer patients, since positive rates were significantly higher in cases with liver metastasis than in those in the non-liver metastasis group.
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PMID:5'-Nucleotide phosphodiesterase isozyme-V in hepatocellular carcinoma and other liver diseases. 170 10

We have determined the effect of forskolin, an adenyl cyclase agonist, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, on the accumulation and cytotoxicity of cisplatin (DDP) in 2008 human ovarian carcinoma cells. In DDP-sensitive 2008 cells, forskolin and IBMX caused 2.1-fold and 2.3-fold increases, respectively, in the short-term accumulation of DDP relative to untreated cells. The inactive analogue, 1,9-dideoxyforskolin, decreased DDP accumulation. Forskolin and IBMX also increased accumulation in A2780 cells. Neither forskolin nor IBMX had any effect on DDP accumulation in DDP-resistant 2008 cells. The effects were detectable as early as 1 min and persisted at 60 min. The concentrations for half-maximal stimulation of DDP accumulation were approximately 0.2 microM for forskolin and 0.2 mM for IBMX. Forskolin caused marked increases in cAMP levels in both sensitive and resistant 2008 cells within 1 min, although there were differences in the subsequent time-courses of the response. Both 2008 cell types had identical cAMP-dependent protein kinase (PKA) activity. These results suggest that there is a target downstream of PKA that is an important participant in DDP accumulation, and that this target is defective or missing in DDP-resistant cells. Following a 1-hr exposure to drugs, forskolin and IBMX at concentrations that were by themselves completely non-toxic increased the slopes of the clonogenic survival vs. DDP concentration curves in 2008 cells 1.9-fold and 3.3-fold, respectively. In DDP-resistant 2008 cells, however, forskolin and IBMX increased the slopes only 1.2 and 2.6-fold, respectively. These effects of forskolin and IBMX on DDP cytotoxicity did not directly correlate with the effects on the 1-hr DDP accumulation which suggested that, in addition to modulating DDP accumulation, these agents increase the cytotoxicity of the intracellular platinum. The results indicate that modulation of cAMP levels can have important effects on DDP accumulation and cytotoxicity in 2008 cells and that these effects are significantly diminished in DDP-resistant cells.
Int J Cancer 1991 Jul 30
PMID:Modulation of cis-diamminedichloroplatinum(II) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells. 171 75


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