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)

The biochemical properties of cyclic nucleotide phosphodiesterases in a nonmetastasizing and a spontaneously metastasizing rat mammary carcinoma were compared. The phosphooiesterases in both tumors had a pH optimum of around 8.0 and preferentially hydrolysed cyclic purine nucleotides. The rate of hydrolysis of purine nucleotides in the nonmetastasizing tumor was two times higher than in the metastasizing tumor, but the rate of pyrimidine nucleotide hydrolysis was equal in both tumors. Theophylline, caffeine, and D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro20-1724) inhibited the enzyme activity in both tumors; the percent inhibition was the same by each inhibitor. The cyclic nucleotie phosphodiesterase activity in either tumor was stimulated by Mg++, Mn++, and Co++ and suppressed by Ca++, Zn,++, and Ni++. EDTA inhibited the activity below the basal level (activity in the absence of added cation), an this inhibition could be recovered up to the basal level by an equimolar quantity of either Mn++ or Mg++. Further stimulation of the enzyme activity with increasing concentrations of divalent cations was observed only with Mn++. Similar effects were observe with ethylene glycol bis(beta-aminoethyl ether)-tn,n-tetraacetic acid. The stimulatory cations affected both the low and high Michaelis constant (tkm) enzymes in these tumors by increasing the maximum velocity. In the low Km enzyme, the Km was also slightly increased. Neither guanosine 3',5'-cyclic monophosphate nor adenosine 3',5'-cyclic monophosphate had any effect on the hydrolysis of the other at physiologic levels.
J Natl Cancer Inst 1976 Jan
PMID:Biochemical properties of cyclic nucleotide phosphodiesterase in metastasizing and nonmetastasizing rat mammary carcinomas. 0 60

Adenosine 3',5'-cyclic monophosphate (cAMP) may be one of the important factors in regulating the expression of many differentiated functions in neuroblastoma cells, but some of these functions can be induced by agents that do not increase the intracellular level of cAMP. An elevation of the intracellular level of guanosine 3',5'-cyclic monophosphate (cGMP) neither induced differentiation nor antagonized the effects of cAMP. Neuroblastoma cells increased the level of cAMP-binding proteins during differentiation, whereas glial cells and L-cells did not. This might have accounted in part for an increase in the intracellular level of cAMP even in the presence of high phosphodiesterase activity in neuroblastoma cells, since the protein-bound with the same proteins, but cAMP had about 10 times higher affinity than did cGMP. cAMP promoted the organization of microtubules and microfilaments necessary for the expression of differentiated phenotypes. The extension of neurites required the synthesis of new protein, but it did not need the synthesis of new RNA. cAMP induced differentiation in neuroblastoma cells by increasing the expression of some genetic information while suppressing the expression of others; e.g., the activities of neural enzymes increased, whereas the synthesis of histone and the phosphorylation of H1-histone markedly decreased in differentiated cells. A hypothesis was offered: An increase in cAMP phosphodiesterase activity as a result of mutation in the regulatory gene for phosphodiesterase in a single, or group of, dividing nerve cell(s) is the primary lesion that leads to malignancy. Based on the concept that selective cytocytoxic drugs should be used with agents that cause differentiation, a new therapeutic approach was suggested for the treatment of neuroblastoma. This involved administration of sodium butyrate followed by L-DOPA or prostaglandin E1 in the presence of cAMP phosphodiesterase inhibitor followed by the less immunosuppressive vincristine and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide.
J Natl Cancer Inst 1976 Sep
PMID:Cyclic nucleotides in the regulation of expression of differentiated functions in neuroblastoma cells. 1 Apr 49

Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-forzen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction (31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, failed to alter cGMP levels inslices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN3, NH2OH, and NaNO2 were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.
Cancer Res 1977 Jan
PMID:Increased guanylate cyclase activity and guanosine 3',5'-monophosphate content in ethionine-induced hepatomas. 1 87

Adenylate cyclase activity as well as intracellular content of sAMP were decreased 2.5-4-fold, as compared with normal state, in plasmatic membranes (PM) of hepatoma 22 and of Ehrlich ascites carcinoma--the tumors characterized by high level- of malignancy. Activity of cAMP phosphodiesterase exceeded distinctly the normal value in all the tumors studied. In less malignant hepatoma 48 the adenylate cyclase activity and content of cAMP were similar to those found in normal liver cells. The guanylate cyclase activity did not differ markedly from values found in normal liver cells in PM of all the tumors studied and in liver tissue of the tumor-bearing animals. Distinct alterations were not found in content of cGMP in the tumors, except of hepatomas 60 and 22, in which the nucleotide level exceeded 2-fold the normal value. The ratio cAMP/cGMP was decreased in the most malignant tumors. At the same time, the ratio was distinctly elevated in tumors with the middle level of malignancy (hepatomas 60 and 61).
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PMID:[Concentration of cyclic nucleotides, activity of adenylate cyclase, 3',5'-AMP phosphodiesterase and guanylate cyclase in plasma membranes from liver and hepatomas of different degrees of malignancy]. 3 Feb 12

The influence of some biogenic amines and amine-receptor-blocking drugs in the growth rate of human colorectal carcinomas propagated as s.c. xenografts in immune-deprived mice was studied. In mice treated with adrenaline, a beta-adrenergic agonist, the growth of xenografts was suppressed for 2 days, after which growth was resumed at a rate similar to that in control animals. Treatment with the phosphodiesterase inhibitor theophylline prolonged the adrenaline-induced inhibition of growth. Treatment with the beta-adrenergic antagonist sotalol or practolol increased the rate of tumour growth. Treatment with either serotonin or the histamine H2-receptor agonist Dimiprit had no effect on tumour growth rate. However, the antiserotoninergic drug BW 501C and the histamine H2-receptor antagonist cimetidine each caused short-term suppression of tumour growth.
Br J Cancer 1979 Nov
PMID:Influence of biogenic amines on the growth of xenografted human colorectal carcinomas. 4 63

The activity of the phosphodiesterase enzyme(s) responsible for the degradation of cylic adenosine monophosphate (CA.M.P.) and cyclic guanosine monophosphate (CG.M.P. (in human normal and carcinomatous lung tissue has been investigated. Enzyme activities were 3-5 times greater in normal than in carcinomatous lung. This is compatible with the known higher concentrations of these cyclic nucleotides in normal tissues. It is suggested that cancer chemotherapy designed to block the phosphodiesterase activity, and thus promote accretion of CA.M.P and CG.M.P., may provide a means of normalising cancerous tissue. Both phosphodiesterase activities in both types of tissue were inhibited by methylxanthines at 10(-3) mol/l, but some enzyme potentiation was observed at lower concentration.
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PMID:Cyclic nucleotide phosphodiesterase activity of human normal and carcinomatous lung tissue. 6 44

It has been demonstrated previously that nontransformed C3H/10T1/2CL8 mouse embryo fibroblasts (10T1/2) can induce a state of reversible growth inhibition in cocultured malignantly transformed mouse fibroblasts and that this inhibition is modulated by serum concentration. The present study suggests that cyclic nucleotides may be implicated in this intercellular communication. The phosphodiesterase inhibitors theophylline, caffeine, and 3-isobutyl-1-methylxanthine (IBX) at concentrations of 10(-3) M, maintained continuously, were all found to inhibit the expression of 3-methylcholanthrene-induced malignant transformation when added 7 days after removal of carcinogen. IBX was the most potent, causing 100% inhibition at 10(-4) M and 70% inhibition at 10(-5) M. This inhibition was partially reversible in the former case and completely reversible in the latter case by removal of drug. Complete inhibition by 10(-4) M IBX was still observed when treatment was delayed 21 days postcarcinogen. In reconstruction experiments, utilizing confluent monolayers of 10T1/2 cells overlaid with transformed cells, IBX caused a dose-dependent inhibition of colony size of the transformed cells. Adenosine cyclic 2':3'-monophosphoric acid (cAMP) and N6,O2'-dibutyryladenosine cyclic 3':5'-monophophoric acid potentiated this response. The presence of non-transformed 10T1/2 cells was required for this effect, since a concentration of IBX (10(-4) M) inhibitory for the growth of transformed cells in mixed cultures was without effect on the growth rate, plating efficiency, or saturation density of pure cultures of 10T1/2 cells or of their transformed counterparts. Conditioned medium removed from IBX-treated 10T1/2 cells was not growth inhibitory for transformed cells, indicating a requirement for cell-cell contact. IBX caused a dose-dependent increase in intracellular cAMP in confluent 10T1/2 cells and a more pronounced increase in cAMP concentration in the culture medium of these cells. The dose-response effects of IBX on growth inhibition of malignant cells in mixed cultures appear to correlate well with its ability to elevate cAMP levels. Thus, IBX increased the capacity of 10T1/2 cells to cause reversible growth arrest of transformed cells and appears to act in a manner analogous to the previously reported effects of serum.
Cancer Res 1979 Sep
PMID:Modulation of cellular interactions between C3H/10T1/2 cells and their transformed counterparts by phosphodiesterase inhibitors. 8 99

The adenosine-3, 5-cyclic monophosphate phosphodiesterase (cPDE) activity in the homogenates of 6 spontaneously metastasizing, nonimmunogenic, glycocalyx-shedding rat mammary carcinomas (MT) was assayed and compared with four histologically and growth rate-matched nonmetastasizing, immunogenic MT. The levels of this enzyme were 2.5 times higher in the nonmetastasizing tumors. To rule out the possibility of the presence of inhibitor(s) or stimulator(s) of cPDE, homogenates from a nonmetastasizing and from a widely metastasizing tumor were mixed. cPDE from both nonmetastasizing and metastasizing MT showed two apparent Km and two corresponding Vmax. The activity of the enzyme at concentrations of 1 muM (low Km) and 100 muM (high Km) adenosine-3, 5-cyclic monophosphate (cAMP) decreased in parallel with increasing metastasizing capacity. About 50% of the low and the high Km cPDE was in the cytosol in both groups, whereas the rest was particulate. The proportion of low and high Km activity was similar in all the fractions except in the plasma membrane of the metastasizing tumors where the percent of low Km enzyme was three times higher than that of the high Km. The steady-state levels of cAMP were 1.3-2.0 times higher in the metastasizing tumors, inversely proportional to their cPDE activities.
J Natl Cancer Inst 1975 Jan
PMID:Adenosine-3',5'-cyclic monophosphate levels and adenosine-3',5'-cyclic monophosphate phosphodiesterase activity in metastasizing and nonmetastasizing rat mammary carcinomas. 16 15

The total cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase activities as well as the activities of the low- and high-K-m enzyme forms were investigated in homogenates, 100,000 X g supernatants, and plasma membrane fractions of rat liver and Morris hepatoma 5123tc(h); the responsiveness of hepatoma and liver plasma membrane (low-K-m) phosphodiesterases to imidazole (40 mM) and theophylline (5mM) were also compared at cAMP concentrations of 1 and 7.5 muM. The total cAMP phosphodiesterase activities of tumor homogenates and 100,000 X g supernatant fractions were found to be less than one-half those of liver; kinetic studies of homogenates indicated that this finding was largely due to a substantial reduction (53%) in activity of the hepatoma high-K-m enzyme. In contrast, low-Km cAMP phosphodiesterase activities for tumor homogenate and plasma membrane fractions were significantly (50%) higher than liver; this was particularly evident when cAMP concentrations were between 0.5 and 2 muM. Since these concentrations are in the range of basal physiological levels of cAMP in hepatocytes, the present results suggest that the reduced levels of cAMP, previously observed in hepatoma 5123tc (h), are primarily due TO An increased rate of cAMP metabolism by low-Km cAMP phosphodiesterase in plasma membranes of the tumor. Imidazole increased the activity of the low-K-m cAMP phosphodiesterase of liver plasma membranes by 22 (1 muM cAMP) and 38% (7.5 muM camp); tumor activity was enhanced 35 and 50%, respectively, at 1 and 7.5 muM cAMP. Theophylline inhibited the plasma membrane phosphodiesterase activity of liver 79 and 53% at cAMP concentrations of 1 and 7.5 muM, respectively; hepatoma activity was inhibited 82 (1 muM cAMP) and 62% (7.5 muM cAMP).
Cancer Res 1975 Mar
PMID:Increased activity of low-Km cyclic adenosine 3':5'-monophosphate phosphodiesterase in plasma membranes of Morris hepatoma 5123tc (h). 16 86

The hypothesis that hepatitis B infection is etiologically related to hepatoma has been investigated by studying the interrelationships between hepatitis B surface antigen (HBsAg, Australia antigen) and the fast-moving 5'-nucleotide phosphodiesterase Band V isoenzyme (5'-NPDase-V). Sera from 58 patients with viral hepatitis were tested for 5'-NPDase-V and HBsAg. The isoenzyme was found in 34 of 37 patients who were also positive for HBsAg but in only 4 of 21 hepatitis patients who were HBsAg negative. Five patients convalescing from hepatitis were negative for both HBsAg and the isoenzyme. Preparative gel electrophoresis showed that these 2 markers were different proteins. Of 34 hepatoma patients, 29 were positive for 5'-NPDase-V. Only 1 isoenzyme-positive patient was positive for HBsAg by counterimmunoelectrophoresis. However, of 16 isoenzyme-positive hepatoma patients available for radioimmunoassay, 8 were NBsAg positive (50%). None of 21 hepatoma samples tested for antibody to NBsAg was positive. Of 21 "normal" carriers of HBsAg and 10 carriers with Down's syndrome, 4 persons were detected with the isoenzyme. The results suggest that HBsAg and 5'-NPDase-V in the presence of liver damage are associated and thus provide a new marker enzyme between hepatitis B infection and hepatoma.
Cancer Res 1975 Sep
PMID:5'-nucleotide phosphodiesterase isoenzyme in patients with hepatitis B infection. 16 56


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