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)

A 2-year prospective study testing 258 breast cancer patients for the presence of 5'-nucleotide phosphodiesterase isozyme-V (5'-NPD-V) as a marker for liver metastases was undertaken. Despite the difficulty associated with such a study in obtaining data from biopsy (only 12 patients) and autopsy (only 18 patients), the 5'-NPD-V test correctly predicted confirmed liver metastases in 39 of 41 patients (95%). Of this group, 25 patients had abnormal liver scans at the time the 5'-NPD-V test was positive (64%). In 11 of 39 patients 5'-NPD-V was found positive before liver scans. In the majority of patients, 5'-NPD-V fluctuated between positive and negative during follow-up. While such transiently positive values may be related to treatment, they should be interpreted conservatively as liver proliferation until confirmed otherwise. Throughout the 2-year study only seven patients with nonmalignant hepatic diseases had consistent positive values (2.7%). As an indicator of liver metastases 5'-NPD-V is more specific than other liver function tests. It is also important to note that 14 patients received early chemotherapy because attention was directed toward the diagnosis of liver metastases by this test.
Cancer 1984 Nov 01
PMID:5'-Nucleotide phosphodiesterase isozyme-V as a marker for liver metastases in breast cancer patients. 609

Intracellular levels of cyclic AMP and cAMP phospodiesterase activity of peripheral blood mononuclear cells of patients with Hodgkin's disease (HD) were studied. The cAMP levels were elevated by 137% in HD patients as compared to normal subjects. The levels were reduced during clinical remission but remained significantly higher than normal controls. These high levels of cAMP in HD patients may be due to reduced degradation of cAMP as the cAMP phosphodiesterase activity was reduced to 50% of normal. This observed altered metabolism still persisted even after depletion of adherent monocytes, indicating that the defect was in the lymphocytes.
Eur J Cancer Clin Oncol 1984 Nov
PMID:Cyclic AMP metabolism in peripheral blood lymphocytes from patients with Hodgkin's disease. 609 95

Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable inall mononuclear-leucocyte preparations with the methods used.
Br J Cancer 1980 Mar
PMID:Patterns of cyclic nucleotides in normal and leukaemic human leucocytes. 610 1

2,131 coded sera were obtained and tested according to the new 5'-NPDase-V isozyme test. On decoding, 99/126 (79%) samples of primary hepatoma, from the United States and other countries, were positive. In the U. S. group, 51/58 (88%) were positive, 23/58 (40%) had AFP higher than 20 ng/ml. In the non-U. S. group, 48/68 (71%) were positive for 5'-NPDase-V, as compared with AFP elevation in 45/68 (66%). 236/268 (88%) cases of cancer with known liver metastases were positive for 5'-NPDase-V. Of 1,040 cancer patients without liver scan or biopsy evidence of metastasis, 316 were positive. In a follow-up of this group of 316 cases, 109 underlying liver metastases were demonstrated by repeat scan or at autopsy within 3--6 months. All 166 sera from normal healthy persons were negative for 5'-NADase-V. Based on this large panel, 5'-NPDase-V test is a sensitive and an important diagnostic aid for cancer patients, both as an early predictor for liver metastases, and a useful marker for primary hepatoma when no other primary sites are found and when there is no evidence of severe chronic liver disease such as cirrhosis.
Cancer 1980 Jan 15
PMID:Serum 5'--nucleotide phosphodiesterase isozyme--V test for human liver cancer. 615 48

The antiproliferative effect of human fibroblast interferon (IFN-beta), human recombinant leukocyte interferon (IFN-alpha A), and polyinosinic . polycytidylic acid [poly(I) . poly(C)] was investigated in human colon carcinoma cell line HT-29. Exposure of HT-29 cells for 1 to 3 days with 100 to 2000 units of either interferon preparation resulted in a 30 to 50% inhibition of growth after 3 days. Similar treatment of cells with 100 micrograms per ml poly(I) . poly(C) resulted in progressive inhibition of growth by 50 to 60% in 2 to 3 days. The inhibitory effects of combination of either IFN-beta or IFN-alpha A with poly(I) . poly(C) were additive with up to 80 to 90% inhibition of cell growth after 3 days of exposure. None of the treatment regimens was markedly cytocidal, and only 25 to 30% reduction in colony formation was noted under optimal treatment conditions following 2 to 3 days of drug exposure. Measurements of DNA, RNA, and protein synthesis following interferon treatment indicated a dose-dependent reduction in all three parameters, particularly when interferon was administered with poly(I) . poly(C). The associated changes in the (2',5')oligoadenylate [(2',5')oligo(A)] pathway produced by IFN-beta and IFL-alpha A were measured under growth-inhibitory conditions. A concentration-dependent induction of (2',5')oligo(A) synthetase was produced by IFN-beta or IFL-alpha A with a concomitant decrease in (2',5')oligo(A) phosphodiesterase. Poly(I) . poly(C) alone induced (2',5')oligo(A) synthetase activity but had no effect on the associated activity of phosphodiesterase. The combination of either IFN-beta or IFL-alpha A and poly(I) . poly(C) further reduced (2',5')oligo(A) phosphodiesterase activity. There was no general dose-response correlation between the induction of (2',5')oligo(A) synthetase and the cytostatic activity of interferon treatment alone or in combination with double-stranded RNA.
Cancer Res 1983 Jun
PMID:Effects of fibroblast and recombinant leukocyte interferons and double-stranded RNA on ppp(2'-5')An synthesis and cell proliferation in human colon carcinoma cells in vitro. 618 84

The mechanisms of action of, and resistance to, important anticancer agents are briefly described. Their selective toxicity is considerably high, and is chiefly due to the distribution and metabolism in the body. The selective toxicity of some DNA-binding drugs may be attributed to the structural difference of DNA, nucleosome and/or chromatin between neoplastic and normal cells. Some studies of reducing side effects are summarized. In our laboratory, we are studying drug-resistance and metastasis of tumor cells. Since the mechanism of natural resistance of gastric cancer, pulmonary cancer, and other refractory cancers may be related to acquired resistance of leukemia, studies on new agents against drug-resistant tumor cells are important. In our laboratory, we have selected cell sublines of murine T-lymphoblastoma L5178Y for resistance to adriamycin (ADM), aclarubicin (ACR) or bleomycin (BLM), and have observed that the resistance is attributed to decreased influx and increased efflux of the antibiotic, resulting in lowered retention of the drug in the cells. Each resistant subline shows a characteristic cross-resistant pattern, suggesting that membrane alteration involved differs each other. We have also found that glycoprotein-synthesizing activity and alkaline phosphodiesterase activity of plasma membrane are higher in the three resistant sublines than in the parental cell line. We obtained a number of hybridomas producing antibodies to plasma membrane of an ACR-resistant subline of L5178Y cells. Among the syngeneic monoclonal antibodies, one was found by agglutination tests to react with the ACR-resistant cell line, but not significantly with the parental and ADM-, BLM-and MCR-resistant cell lines. Fluorographs of [14C] leucine-labeled ACR-resistant cells demonstrates two protein bands of 230 K and 20 K daltons, which are precipitated by the monoclonal antibody. The former seems to be specific to the ACR-resistant cells. Based on the results so far obtained, the 230 K protein may be related to the drug resistance and may be TATA (tumor-associated transplantation antigen). The results suggest that isolation of drug-resistant neoplastic cells is a novel method of finding TATA.
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PMID:[Mechanism of action and resistance of antineoplastic agents]. 619 71

Four types of 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates with poly-L-glutamic acid (PLGA) or poly-N5-(2-hydroxyethyl)-L-glutamine (PHEG) were prepared in an attempt to enhance the efficacy of the drug in simple dosage schedules. The conjugates were made by linking ara-C to the carboxyl groups of PLGA directly at N-4 of ara-C (ara-C:PLGA) or indirectly through the 2-aminoethylphosphoryl or 6-aminohexylphosphoryl side chain which had been introduced to C-5' of ara-C, 1-[5'-(2-aminoethylphosphoryl)-beta-D-arabinofuranosyl]cytosine: PLGA [araCMP(C2):PLGA and 1-[5'-(6-aminohexylphosphoryl)-beta-D-arabinofuranosyl]cytosine:++ +PLGA, respectively, or made by converting the remaining carboxyl groups in the PLGA conjugates to the 2-hydroxyethylamide groups [ara-C:PHEG, ara-CMP(C2):PHEG, 1-[5'-(6-aminohexylphosphoryl)-beta-D-arabinofuranosyl]cytosine:++ +PHEG]. Studies in vitro showed that the conjugates had decreased cytotoxicity against L1210 cells when compared with that of ara-C. Studies in vivo showed that all of the conjugates, except ara-CMP(C2):PLGA, had a greater antitumor activity than did ara-C in L1210 tumor-bearing BALB/c X DBA/2 F, (hereafter called CD2F1) mice (inoculum, 1 X 10(5) cells i.p. on Day 0) which were treated by a single i.p. injection of either the conjugates or the control ara-C on Day 1. The largest antitumor activity [increased life span (ILS) 170%] was observed with a dosage of 50 mg (equivalent ara-C per kg) of ara-C:PHEG. When CD2F1 mice which had been inoculated i.p. with 1 X 10(5) L1210 cells were treated with an i.p. injection of 12.5 or 25 mg (equivalent ara-C per kg) of ara-C:PHEG daily for 5 days starting from Day 1, 2 of 5 mice survived more than 42 days, and the ILS of the remaining mice was 153 and 184%. The injections of 3.2 mg (equivalent ara-C per kg) of ara-C:PHEG showed a moderate antitumor activity with an ILS of 113% which was similar to the ILS (119%) found when unconjugated ara-C (400 mg/kg) was used to treat tumor-bearing mice. In in vitro release experiments, ara-C was released slowly from ara-C:PLGA at pH 7.4, and ara-CMP(C2):PLGA was chemically stable but cleaved by phosphodiesterase, acid phosphatase, and alkaline phosphatase to give mainly 1-beta-D-arabinofuranosylcytosine 5'-monophosphate.
Cancer Res 1984 Jan
PMID:Antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugated with polyglutamic acid and its derivative. 619 62

Recent studies have suggested that cyclic AMP (cAMP) may be involved in regulation of cell growth and differentiation of cancer cells. Incubating HL-60 cells in the presence of the specific H2 agonist dimaprit resulted in 30-fold increases in cAMP levels (EC50 = 5.7 X 10(-6) M) and morphological changes suggestive of cell maturation along the granulocyte pathway. However, cells cultured with 10(-5) M dimaprit showed more than an 80% decrease in their cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 was unaltered. Desensitization was time-dependent (halftime approximately 2.5 hr with 10(-5) M dimaprit), dose-dependent (dimaprit EC50 = 1.4 X 10(-6) M) and completely prevented by 10(-3) M cimetidine. Desensitization of HL-60 cells for 4 hr with 10(-5) M dimaprit followed by the addition of 10(-3) M cimetidine resulted in total recovery of the cAMP response in less than 24 hr. The pharmacologically inactive analog N-methyldimaprit (SK&F 92054) did not increase cAMP production or cause desensitization to H2 stimulation. Desensitization was observed in the presence or absence of a phosphodiesterase inhibitor, indicating that induction of cAMP-phosphodiesterase was not involved in this process. No difference in the number of [3H]tiotidine binding sites was observed between control and dimaprit-desensitized HL-60 cells. Based on these results, we suggest that H2 receptor agonists caused an agonist-dependent desensitization, presumably due to an uncoupling of receptors from adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histamine H2 receptor desensitization in HL-60 human promyelocytic leukemia cells. 620 54

An abnormal, fast-moving 5'-nucleotide phosphodiesterase isozyme was found in 90.0% of 20 Malaysian patients with primary hepatoma and in 23.5% of 391 Malaysian patients with various malignant diseases; it was also discovered in 42.9% of 14 Malaysian and American patients with clinically active hepatitis B infection; in 16.7% of 18 healthy American blood bank donors who were positive for hepatitis B surface antigen (HBsAg); in 13.9% of 287 healthy Malaysian blood bank donors, some positive for HBsAg; and in none of 160 healthy American donors who were negative for HBsAg. A correlation of this abnormal isozyme with hepatoma and with infectious hepatitis B is clearly evident.
Cancer 1980 Feb 15
PMID:5'-Nucleotide phosphodiesterase isozyme-V in health, in cancer, and in viral hepatitis. 624 75

A series of experiments evaluated the antileukemic effect of an agent which elevates cellular cyclic adenosine 3':5'-monophosphate levels by phosphate levels by inhibiting phosphodiesterase. When administered alone, theophylline had only modest antileukemic effects, but it had synergistic effects when administered with 1,3-bis(2-chloroethyl)-1-nitrosourea. This synergism produced an improved therapeutic index in a dose-response study and in a comparison between antileukemic effects and effects on white blood cell nadirs. Uptake of 1,3-bis(2-chloroethyl)-1-nitrosourea and studies of timing of treatment support the hypothesis that elevation of cyclic adenosine 3':5'-monophosphate levels is the mechanism of the observed synergistic effect.
Cancer Res 1980 Jul
PMID:Synergistic antileukemic effect of theophylline and 1,3-bis(2-chloroethyl)-1-nitrosourea. 624 98


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