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

In 1986, we reported that abnormal 5'-nucleotide phosphodiesterase (5'-NP) (oligonucleate: 5'-nucleotidohydrolase, EC 3.1.4.1) isoenzymes (5'-NP I and 5'-NP V + VI) were observed in the serum of patients with liver cancer. The results of the present study show that the 5'-NP I positivity rate is 99.2% (234/236), specificity 74.9%; and the 5'-NP V + VI positivity rate is 77.5% (183/236), specificity 95.3% in liver cancer. 5'-NP I positivity rate is 86.7% (13/15) and 5'-NP V + VI positivity rate is 46.7% (7/15) in metastatic liver cancer. These 3 abnormal isoenzyme bands were all present in the serum of 6 patients with liver cancer before radical resection and disappeared after successful resection, but they were all present in the serum of 6 other liver cancer patients before and after palliative operation. In 2 cases of small liver cancer (diameter less than 4cm), 5'-NP I and 5'-NP V + VI were strongly positive. It may be considered that the new 5'-NP abnormal isoenzyme bands are specific markers and will be useful for diagnosis of human liver cancer.
Int J Cancer 1988 Jan 15
PMID:The significance of new abnormal isoenzymes of 5'-nucleotide phosphodiesterase in the diagnosis of human liver cancer. 282 44

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.
J Natl Cancer Inst 1988 Mar 16
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

We have previously demonstrated that, by elevating intracellular adenosine 3':5'-cyclic monophosphate (cAMP) levels by inhibition of cAMP phosphodiesterase with Ro 20-1724 or by forskolin stimulation of adenylcyclase, the growth of neoplastically transformed 10T1/2 fibroblasts could be inhibited when these cells were in contact with growth-inhibited nontransformed 10T1/2 cells (J. S. Bertram and M. B. Faletto, Cancer Res., 45: 1946-1952, 1985) and furthermore that the extent of this growth inhibition correlated strongly with the degree of junctional communication between the two cell types (P.P. Mehta et al., Cell, 44: 187-196, 1986). To determine if these treatments enhance the degree of growth control of the nontransformed 10T1/2 cells, cultures were exposed to varying concentrations of Ro 20-1724 and/or forskolin. Drug treatment caused no significant effects on growth rate or cell spreading when cells were treated during logarithmic growth phase; however, major reductions of up to 70% in confluent saturation density and concomitant increases in cell spreading occurred in cultures making extensive cell/cell contacts. Decreases in saturation density correlated strongly with induced elevations of both intra- and extracellular cAMP concentrations. These effects could not be duplicated by the addition of exogenous cAMP agonists 8-bromo-cAMP and/or dibutyryl-cAMP. Two-dimensional electrophoresis of phosphate-labeled proteins revealed that forskolin treatment induced a quantitatively and qualitatively different phosphorylation profile than did 8-bromo-cAMP. Both basal and drug-induced intracellular cAMP levels fell as cells progressed from logarithmic to confluent growth state, implying that cells become sensitized to cAMP by the attainment of extensive cell/cell contacts. It is suggested that the drug-induced elevations of endogenously synthesized cAMP are accentuating a physiological role of cAMP on the postconfluent growth arrest of murine fibroblasts. The requirements for cell/cell contact and the known increased junctional communication induced by cAMP furthermore suggest that cAMP is enhancing the junctional transfer of a growth-inhibiting regulatory molecule. A likely candidate is cAMP itself.
Cancer Res 1988 Apr 01
PMID:Augmentation of postconfluence growth arrest of 10T1/2 fibroblasts by endogenous cyclic adenosine 3':5'-monophosphate. 283 54

Regulation of insulin release, membrane potential, transmembrane 45Ca fluxes and cytoplasmic free Ca2+ concentration, [Ca2+]i, was examined using suspensions of transplantable NEDH rat insulinoma cells previously cultured for 2-3 days to eliminate necrotic tumour cells and counter prior hypoglycaemia. Insulinoma cells displayed a resting [Ca2+]i of 94 +/- 8 nM (n = 17) and released 104 +/- 15 ng insulin 10(-6) cells (n = 7) during 60 min incubations with uptake of 2.7 +/- 0.2 nmol 45Ca 10(-6) cells (n = 7). High concentrations of glucose did not affect membrane potential, transmembrane 45Ca fluxes, [Ca2+]i or insulin release by insulinoma cells. K+ at 25 mM depolarised the plasma membrane, induced a small increase in 45Ca efflux and increased [Ca2+]i by 65%. This modest action was not associated with demonstrable effects on 45Ca uptake and insulin release. The effect of 25 mMK+ on [Ca2+]i was counteracted by D-600, but this blocker of voltage-activated Ca2+ channels and verapamil lacked effects on transmembrane 45Ca fluxes and insulin release. The Ca2+-calmodulin antagonist, trifluoroperazine, was also without effect on 45Ca fluxes and insulin release. Ca2+ ionophore ionomycin increased [Ca2+]i, whereas A23187 and X537A did not affect transmembrane 45Ca fluxes. Moreover, insulin release was independent of extracellular Ca2+ over the range 0-20.4 mM despite marked affects on transmembrane 45Ca fluxes and a greater than 4-fold change of [Ca2+]i. Dibutyryl cyclic AMP increased insulin release by 55% without affecting transmembrane 45Ca fluxes or [Ca2+]i. The phosphodiesterase inhibitor, theophylline, also enhanced insulin release by 10-36% with no change of 45Ca uptake. The effectiveness of theophylline was independent of extracellular Ca2+ over the range 0-10.2 mM. These results indicate that inappropriate Ca2+ regulation is a key pathogenic feature underlying the inappropriate insulin secretion of rat insulinoma cells.
Br J Cancer 1988 Jul
PMID:Measurements of membrane potential, transmembrane 45Ca fluxes, cytoplasmic free Ca2+ concentration and insulin release by transplantable rat insulinoma cells maintained in tissue culture. 284 19

Soluble, high-affinity cyclic adenosine 3':5'-monophosphate (cyclic AMP) phosphodiesterases extracted from blast cells of patients with acute myelogenous leukemia have been characterized by physical, kinetic, and immunological criteria and fractionated to a high degree of purity. Procedures used in this study were similar to those used to purify the high-affinity enzyme from dog kidney. Two forms of high-affinity enzyme were found in blast cells. Form A was similar to the known type IV phosphodiesterases, including those of normal lymphocytes and monocytes. It showed a molecular weight near 60,000, a rate of hydrolysis of cyclic AMP 7 to 10 times that of cyclic guanosine 3':5'-monophosphate (cyclic GMP), competitive inhibition by cyclic GMP for cyclic AMP hydrolysis, and identical immunoreactivity by Western transfer analysis. This enzyme form was purified to apparent homogeneity by physical criteria but showed a low maximum velocity relative to other phosphodiesterase forms. A second, different form of high-affinity phosphodiesterase (Form B) was also resolved and partially purified. By comparison with Form A, this enzyme eluted from diethylaminoethyl cellulose at slightly lower ionic strength, had a lower molecular weight, appeared specific for cyclic AMP as substrate, showed no inhibition of cyclic AMP hydrolysis by cyclic GMP, and displayed no immunological cross-reactivity to the Mr 60,000 enzyme. Neither enzyme form was activated by calmodulin or proteolysis, whereas both showed comparable inhibition by 6,7-dimethoxy-1-veratrylisoquinoline, 1-methyl-3-isobutylxanthine, and 1,3-dimethylxanthine.
Cancer Res 1985 Mar
PMID:Purification and characterization of high-affinity cyclic adenosine 5'-monophosphate phosphodiesterases from human acute myelogenous leukemic cells. 298 89

This study was conducted to further characterize the previously described phenomenon of growth inhibition of neoplastically transformed C3H/10T1/2 cells (T10T1/2) by nontransformed C3H/10T1/2 clone 8 mouse embryo fibroblast (10T1/2) cells in the presence of inhibitors of cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase. The cAMP phosphodiesterase inhibitor dl-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724) was shown to be completely nontoxic to T10T1/2 cells at 10(-4) M, yet when added to mixed cultures of T10T1/2 cells and postconfluence growth-arrested 10T1/2 cells, colony formation and [3H]thymidine incorporation into T10T1/2 cells were virtually eliminated. This effect was dose dependent and was reversible upon drug withdrawal. In 10T1/2 cells, RO20-1724 caused a dose-dependent increase in cAMP levels from about 5 to 150 pmol/10(6) cells; in T10T1/2 cells, 10(-4) M drug treatment caused a 5-fold elevation in cAMP without a clear dose dependency. Cyclic guanosine 3':5'-monophosphate levels in 10T1/2 cells fell by 50% with drug treatment but were unmeasurable in T10T1/2 cells. When intracellular cyclic AMP levels were elevated by the adenyl cyclase stimulator forskolin, growth inhibition of T10T1/2 cells was again induced in mixed cultures but was not observed when added to T10T1/2 cells alone. Addition of RO20-1724 to low concentrations of forskolin produced a greater than additive effect on growth inhibition. Growth inhibition of T10T1/2 cells by RO20-1724 was shown to (a) require contact with, or extremely close proximity to, a confluent monolayer of 10T1/2 cells, (b) be maximum when seeded upon a growth-inhibited monolayer and not an actively growing 10T1/2 culture, and (c) not be decreased by continuous agitation of the culture medium, indicating that readily diffusible inhibitory factors are not involved. A model is presented whereby transformed cells can respond to but cannot themselves generate growth-inhibitory signals produced by post-confluence growth-inhibited nontransformed cells. The existence of these cellular interactions may well explain problems in the quantitation of transformed foci encountered in the use of this cell line as an assay system for chemical and physical carcinogens.
Cancer Res 1985 May
PMID:Requirements for and kinetics of growth arrest of neoplastic cells by confluent 10T1/2 fibroblasts induced by a specific inhibitor of cyclic adenosine 3':5'-phosphodiesterase. 298 40

With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. 298 81

The phosphodiesterase inhibitors caffeine, theophylline, aminophylline and isobutyl-methylxanthine (IBMX) were found to inhibit induction of morphologically transformed hamster embryo cell colonies by sequential exposure to benzo[a]pyrene (BaP) and the tumor promoter TPA. Almost complete inhibition of cell transformation was observed when 50 micrograms/ml theophylline, aminophylline, IBMX, or 200 micrograms/ml caffeine was present together with the tumor promoter. The compounds had no effect on the transformation frequency when present together with the initiator, BaP, in the first exposure period. Substances that stimulate the adenylate cyclase and the addition of exogenous dibutyryl-cAMP had similar inhibitory effects.
Cancer Lett 1985 Aug
PMID:Caffeine and other phosphodiesterase inhibitors are potent inhibitors of the promotional effect of TPA on morphological transformation of hamster embryo cells. 299 64

One hundred endometrium specimens have been studied with flow cytometry for DNA analysis (FCDA) and a proliferative enzyme marker, 5'-nucleotide phosphodiesterase (5'-NPD). FCDA data showed that aneuploidy was present in only 5 of 40 cancer specimens. However, with corrected histograms, a higher DNA value was observed in the G2/M (6%) of all cancer compared with noncancer specimens (4%). Thus, FCDA can be a useful diagnostic aid for endometrial cancer. The determination of 5'-NPD was done with a quenching method based on the use of 5'-(5-iodo-3-indoxyl)-thymidine phosphodiester as a substrate and 4',6-diamidino-2-phenylindole for DNA. This method could qualitatively define which population of the cell cycle had a higher enzyme level and also quantitatively gave the enzyme units per cell. It was found that 12.5% of all cancer specimens had 5'-NPD activity in the G0/G1 cells and 87.5% in the S and/or G2/M cells, whereas in the noncancer specimens 5'-NPD was found in 28.5% of the G0/G1 cells and 71.5% of the specimens had 5'-NPD in the S and/or G2/M cells. Furthermore, the concentration of 5'-NPD was found to be five times higher in the G2/M cells of the cancer specimens than that in the noncancer specimens. However, in the hyperplasia specimens, the activity was only two times higher in the same cell cycle fraction than in the normal specimens. The results of this investigation provided for the first time evidence that this exonuclease activity alters in the cell cycle fractions and that a decrease in the enzyme activity in G0/G1 cells and an increase in G2/M cells may be a useful marker for neoplastic development in human endometrial cancer.
Cancer 1985 Nov 01
PMID:Flow cytometric DNA and 5'-nucleotide phosphodiesterase in endometrium. 299 53

Bombesin/gastrin releasing peptide-like immunoreactivity (BLI) is found in the majority of small cell carcinoma of the lung (SCCL) cell lines examined. Because BLI is present in high concentration in SCCL we studied the mechanism of BLI secretion from several SCCL cell lines and in patients with SCCL. In cell line NCI-H345 the structurally related polypeptide hormones secretin, vasoactive intestinal peptide, and peptide histidine isoleucine as well as theophylline, a phosphodiesterase inhibitor, N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate, a cyclic nucleotide analogue, increased BLI release by 16-120% and cyclic adenosine 3':5'-monophosphate by 36-350%. Similar results were obtained in SCCL cell line NCI-H209. i.v. injection of secretin (2 units/kg) significantly increased plasma BLI in 2 patients with extrapulmonary SCCL. These data suggest that SCCL cells possess receptors for secretin/vasoactive intestinal peptide and that receptor occupation stimulates in vitro and in vivo BLI secretion.
Cancer Res 1986 Mar
PMID:Secretin/vasoactive intestinal peptide-stimulated secretion of bombesin/gastrin releasing peptide from human small cell carcinoma of the lung. 300 12


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