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)

Serum 5'-nucleotide phosphodiesterase isozyme-V (5'-NPDase-V) in 200 patients with various gastrointestinal disorders including 178 malignant cases and 22 benign cases was measured, and the usefulness and limitations of this test for the detection of liver metastasis were studied. Of the laboratory tests performed in the 44 patients with liver metastasis, 5'-NPDase-V and carcinoembryonic antigen (CEA) (greater than 10.0 ng/ml) were positive in 68.2%. This rate was higher than that for any other laboratory test. Positive 5'-NPDase-V assays were found in 46.2% of the patients with H1 metastasis, 70% with H2 and 81% with H3. This test was considered to be useful diagnostically, when liver metastasis was of more than a certain degree. 5'-NPDase-V was positive in 85.7% of the patients who had liver metastasis and had a serum total bilirubin value of more than 2.5 mg/dl. Particular attention should be paid to the evaluation of this test when jaundice is present. In eight of the patients with liver metastasis, CEA (greater than 10.0 ng/ml) was negative, whereas 5'-NPDase-V was positive. One or both of these two markers were positive in 86.4%. A combination assay of these two markers was considered to be more useful than 5'-NPDase-V alone as a screening test for the detection of liver metastasis. In one patient who underwent hepatic lobectomy for recurrence of cancer in the liver, 5'-NPDase-V and CEA were measured before and after the operation. CEA returned to normal immediately after the operation, whereas 5'-NPDase-V became negative five months after the operation. It is presumed that the changes in 5'-NPDase-V after hepatic lobectomy were related to liver regeneration.
 ...
PMID:Diagnostic value of 5'-nucleotide phosphodiesterase isozyme-V for detection of liver metastasis in patients with gastro-intestinal cancer. 631 Jan 82

The growth-inhibitory effect of human immune interferon (IFN-gamma) was investigated in human colon carcinoma cell line HT-29. Three-day treatment of HT-29 cells with IFN-gamma (10 to 200 units/ml) resulted in 30 to 90% growth inhibition and 40 to 99% reduction in colony formation. Measurement of DNA, RNA, and protein synthesis following IFN-gamma treatment showed a dose-dependent reduction in all 3 parameters. The associated changes in (2',5')oligoadenylate [(2',5')oligo(A)] pathway were measured under growth-inhibitory conditions. Upon 1-day exposure to 25 to 200 units/ml of IFN-gamma, (2',5')oligo(A) synthetase activity was induced 10- to 15-fold and remained elevated for 3 days, whereas (2',5')oligo(A) phosphodiesterase activity remained unchanged. There was no detectable increase in intracellular (2',5')oligo(A) levels after IFN-gamma treatment, and ribosomal RNA degradation was not observed. Accompanying 1-day treatment with IFN-gamma (100 units/ml) was an induction of a polyamine-dependent protein kinase, which was double-stranded RNA-independent and phosphorylated endogenous polypeptides with molecular weights of 68,000 and 72,000. A similar exposure of cells to IFN-gamma (25 to 100 units/ml) resulted in 30 to 70% inhibition of ornithine decarboxylase activity; however, no significant alteration in intracellular polyamine levels was observed. These data suggest that IFN-gamma-dependent toxicity is not related to (2',5')oligo(A) activation of a latent endoribonuclease but is accompanied by protein phosphorylation, which is, in part, stimulated by exogenous polyamines.
Cancer Res 1984 May
PMID:Effects of human immune interferon on cell viability, (2',5')oligoadenylate synthesis, and polyamine-dependent protein phosphorylation in human colon carcinoma cells in vitro. 642 36

Calmodulin contents of normal rat liver, host liver [bearing hepatoma 5123t.c.(h)], regenerating liver, and Morris hepatomas 7800, 5123t.c.(h), and 7794A were determined by phosphodiesterase assay and by radioimmunoassay. The calmodulin levels determined by both assays were significantly increased in three hepatomas when compared to the corresponding values of normal liver. The order of increase in calmodulin content was as follows: normal liver = host liver less than 7794A (slow growth rate) less than 5123t.c.(h) (intermediate growth rate) less than 7800 (fast growth rate). In regenerating liver (24 hr after partial hepatectomy), the calmodulin content was not different from that of normal liver. In good agreement with the literature, the calmodulin values measured by the phosphodiesterase assay were always lower than those determined by radioimmunoassay. Calcium and magnesium contents were measured by atomic absorption spectrophotometry in acid digests of these tissues. Both cation contents were significantly increased in the three hepatomas studied when compared to the corresponding values of normal liver; the extent of increase for calcium content (120 to 240%) was much greater than that for magnesium (30 to 40%). The order of increase for both cations was as follows: normal liver = host liver less than 5123t.c.(h) less than 7794A less than 7800. Therefore, there does not appear to be any correlation between the cation contents and hepatoma growth rates. In regenerating liver, magnesium content was about 14% higher than that of normal liver. In summary, the results indicate that only the increase of calmodulin appears to correlate positively with the growth rate of these tumors. This correlation suggests that calmodulin may be involved in tumor cell growth regulation.
Cancer Res 1982 Jul
PMID:Positive correlation between calmodulin content and hepatoma growth rates. 708 50

Murine fibrosarcoma cells (SSK) exhibit a transient cisplatin resistance after low-dose irradiation (5 x 2 Gy) in vitro and in vivo. When resistance is lost, it can be restored by a single drug exposure which, without preirradiation, does not generate cisplatin resistance in parental cells. There is no cross-resistance to radiation. Metallothioneins, which are associated with cisplatin resistance after high-dose irradiation (15 x 6 Gy), do not correlate with induction and loss of cisplatin resistance after low-dose irradiation. Since cisplatin survival curves are also monotonous when drug resistance diminishes, an adaptive response is more likely than a mutational event to underlie cisplatin-induced resistance. Drug resistance can be overcome by combined exposure to cisplatin in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Under these conditions, cisplatin sensitivity is increased 2.4- to 2.8-fold in the resistant strains compared with only 1.5- to 1.8-fold in the parental cells. The cellular platinum content with and without IBMX treatment is not significantly different in sensitive and resistant cells. Loss of drug resistance correlates with a decrease in cisplatin sensitisation by IBMX. This suggests that cisplatin resistance after low-dose irradiation may be associated with alterations of the cAMP-dependent signal transduction pathway.
Br J Cancer 1994 Oct
PMID:Cisplatin resistance in mouse fibrosarcoma cells after low-dose irradiation in vitro and in vivo. 752 9

We transfected mouse 10T1/2 fibroblasts with the H-ras oncogene and isolated lines expressing H-ras. One of the lines exhibited a highly malignant phenotype with the ability to produce large tumors and to colonize the lung after tail vein injection. In addition, the cells of this line showed increased collagenase IV production, directed migration and invasiveness, properties associated with the ability of tumor cells to metastasize. Since cyclic adenosine 3',5'-monophosphate (cAMP) is known to down-regulate ras expression, we exposed the malignant cells (Cl-1) to either N6, 2',0-dibutyryl cAMP (DB-cAMP) or 8-bromo cAMP (8-Br-cAMP), either with or without a phosphodiesterase inhibitor. We found that these treatments reduced the expression of ras, chemotaxis, invasiveness, and lung colonization of the ras-transformed cells. We therefore postulate that the malignancy of some cells may be regulated by alterations in the intracellular cAMP levels by suppressing ras expression and/or by reducing other activities required for the dissemination of tumor cells.
 ...
PMID:Cyclic AMP decreases chemotaxis, invasiveness and lung colonization of H-ras transformed mouse fibroblasts. 769 88

Recent cumulative data have shown that tamoxifen and its metabolites inhibit the activation of cAMP phosphodiesterase by calmodulin (CaM). In this study, the interaction of antiestrogens with CaM was investigated using a hydrophobic fluorescent probe, 2-p-toluidinylnaphthalene-6-sulfonate (TNS). Tamoxifen (TAM) enhanced the fluorescence of TNS bound to CaM and shifted the emission maximum to lower wavelengths. These effects were concentration-dependent. No change in the apparent affinity of TNS for CaM was noted in the presence of TAM. These results suggest that TAM bound to CaM at sites distinct from those of TNS and induced a change in TNS environment. Interaction of TAM metabolites with CaM depended on the degree of alteration of the dimethylaminoethoxy side-chain. Thus, N-desmethylation or N-di-desmethylation notably reduced the interaction of the drug with the macromolecule by 24 and 77% respectively. Side-chain deamination to the primary alcohol (metabolite Y) totally suppressed the interaction. The ability of these different metabolites to interact with CaM correlates with their efficiency to inhibit CaM-dependent cAMP phosphodiesterase and their growth inhibitory potency reported previously.
Cancer Detect Prev 1994
PMID:Fluorimetric studies of calmodulin interactions with antiestrogens. 786 20

Enzymes which traditionally have played no role in cell-directed cytotoxicity are finding their way into schemes for prodrug activation and immunotoxins owing to such useful enzymatic activity. Alkaline phosphatase, carboxypeptidases, beta-glucosidases and beta-lactamases among many others are being utilised to regenerate potent anti-cancer drugs or toxic small molecules from precursors in a bid to enhance their activity in tumours. These prodrug activation systems require the pretargeting of the enzyme to the surface of a tumour cell, usually by an antibody or its immunoreactive fragment. A recent novel approach proposes the intracellular delivery of appropriate enzymes, such as phosphodiesterases, to particular cellular compartments. There, enzyme activity can cause substantive damage resulting in cell death. Cell targeting of mammalian phosphodiesterase promises to improve upon conventional immunotoxins because of their increased cytotoxicity when targeted to the appropriate compartment and their expected lack of, or lower, immunogenicity in clinical use.
Br J Cancer 1994 Nov
PMID:Targeting enzymes for cancer therapy: old enzymes in new roles. 794 82

Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to tiazofurin were developed by drug-selection pressure. Compared to a concentration producing 50% cell proliferation reduction that was 9.1 microM in sensitive cells, the resistant variants displayed concentrations producing 50% cell proliferation reductions of 12 and 16 mM. The activity of the target enzyme, IMP dehydrogenase, was not altered in the resistant cells. Studies on tiazofurin metabolism revealed that resistant variants formed < 10% of the active metabolite, thiazole-4-carboxamide adenine dinucleotide. This correlated with the activity of NAD pyrophosphorylase, the enzyme that synthesizes thiazole-4-carboxamide adenine dinucleotide, which was reduced to 10% in the resistant lines. Concurrently, the activity of thiazole-4-carboxamide adenine dinucleotide phosphodiesterase was elevated in the refractory cells. Compared to the sensitive counterpart, the levels of GMP and NAD were lower in the resistant lines. Guanine salvage activity was decreased in the resistant cells. Basal dGTP and dATP concentrations were elevated in the resistant line; nevertheless, tiazofurin incubation decreased dGTP levels in only the sensitive cells. Although there was no difference in the Km of tiazofurin transport or efflux, the Vmax of uptake of the drug was reduced in the resistant lines. Sensitive and resistant cells exhibit similar cytotoxicity to agents which do not share the mechanism of action of tiazofurin, suggesting that refractory cells are still sensitive to other standard antileukemic drugs.
Cancer Res 1993 May 15
PMID:Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells. 809 64

N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (dG-C8-PhIP) has been shown to be a major adduct in DNA of rats given [3H]PhIP. However, when DNA from organs of rats fed PhIP was analyzed by the 32P-postlabeling method under standard and adduct-intensification conditions, four adduct spots were observed, and 3',5'-pdGp-C8-PhIP was detected as a minor, not a major, adduct spot. Since the three other major adduct spots were suspected to be those of adducted di- or oligo-nucleotides, the 32P-labeled samples were further treated with nuclease P1 and phosphodiesterase I and found to yield only a single adduct spot. The material in this adduct spot was confirmed to be 5'-pdG-C8-PhIP. Thus, using this newly modified 32P-postlabeling method, dG-C8-PhIP was detected as a major adduct in DNA of rats given PhIP.
Jpn J Cancer Res 1994 Feb
PMID:Detection of guanine-C8-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine adduct as a single spot on thin-layer chromatography by modification of the 32P-postlabeling method. 814 91

The 8-chloro analogue of the regulatory molecule, cyclic AMP (cAMP), modulates the intracellular concentrations of cAMP-dependent protein kinases (PKA) and inhibits both in vitro and in vivo growth of several neoplastic cell types. Because 8-chloro-cyclic AMP (8-Cl-cAMP) can be converted to 8-chloroadenosine (8-Cl-adenosine) by serum enzymes contained in cell growth media, we tested whether 8-Cl-cAMP effects were mediated by its adenosine metabolite in normal and neoplastic cell lines of mouse lung epithelial origin. 8-Cl-adenosine, directly added to cells or derived from exogenously applied 8-Cl-cAMP, specifically decreased the intracellular concentration of the type I isozyme of cAMP-dependent protein kinase (PKA I). 8-Cl-adenosine and 8-Cl-cAMP were equipotent at inhibiting cell growth, and elicited similar changes in the proportion of cells in the G1, S, and G2-M phases of the cell cycle. The presence of adenosine deaminase, which converts 8-Cl-adenosine to 8-chloroinosine, completely prevented growth inhibition by 8-Cl-cAMP and the concomitant diminution of PKA I. 8-Cl-cAMP had no discernible effect on cells when its conversion into 8-Cl-adenosine was prevented by 3-isobutyl-1-methyl-xanthene, an inhibitor of phosphodiesterase. 6-(p-Nitrobenzyl)-thioinosine, an inhibitor of adenosine uptake, protected cells from cytostasis, indicating that 8-Cl-adenosine acts intracellularly. 8-Cl-adenosine greatly decreased RI (regulatory subunit of PKA I) and PKA catalytic (C) subunit protein concentrations without affecting RII (regulatory subunit of the PKA type II isozyme) or intracellular cAMP levels. Northern blot analysis of PKA subunit mRNAs following treatment of each cell line with 8-Cl-adenosine demonstrated decreased C alpha mRNA expression, increased RII alpha mRNA, and no change in RI alpha mRNA abundance. Our results indicate that 8-Cl-adenosine inhibits lung cell growth and induces PKA I down-regulation via a cAMP-independent mechanism.
Cancer Res 1993 Jan 15
PMID:8-Chloroadenosine mediates 8-chloro-cyclic AMP-induced down-regulation of cyclic AMP-dependent protein kinase in normal and neoplastic mouse lung epithelial cells by a cyclic AMP-independent mechanism. 838 Feb 55


<< Previous 1 2 3 4 5 6 7 8 9 10