Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine and putrescine (a precursor of polyamines) are formed by histidine decarboxylase (HDC) and ornithine decarboxylase (ODC), respectively. Within a few hours after injection of a lipopolysaccharide (LPS) into mice, HDC is induced in the liver, spleen, lung and bone marrow, and ODC is induced in the liver, spleen and bone marrow. Since LPS is known to stimulate the production of various cytokines, the abilities of various cytokines to induce HDC and ODC in the tissues of mice were examined. IL-2, IL-6, IL-8, IFN gamma and M-CSF were ineffective. IL-1 alpha, IL-1 beta, TNF alpha and TNF beta induced HDC and ODC, as does LPS. On the other hand, GM-CSF and G-CSF induced HDC and ODC only in the spleen and bone marrow within a few hours after their injection. These results suggest that, in addition to their roles in inflammation or immune responses, HDC and ODC are also involved in an early stage of hematopoiesis.
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PMID:GM-CSF and G-CSF stimulate the synthesis of histamine and putrescine in the hematopoietic organs in vivo. 138 20

The author has studied the effects of alpha-difluoromethylornithine (alpha DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase; human fibroblast interferon (IFN beta); and their combination on human gastric cancer cell growth in vitro. alpha DFMO (from 0.1 to 4 mmol/l) inhibited cell growth in a dose-dependent manner. Both alpha DFMO (0.1 mmol/l) and higher doses of IFN beta (100 and 1000 IU/ml) caused only limited inhibition of cell growth. When alpha DFMO (0.1 mmol/l) was administered in combination with IFN beta (100 and 1000 IU/ml), synergistic antiproliferative activity was observed 7 days after continuous exposure. Although the mechanisms by which this effect occurs are unclear, it appears to be associated with direct inhibition of tumor cell proliferation, possibly by modulation of polyamine metabolism.
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PMID:Synergistic antiproliferative activity of human fibroblast interferon in combination with alpha-difluoromethylornithine against human gastric cancer cells in vitro. 156 61

DFMO and IFN have both been shown to suppress the intracellular activity of ornithine decarboxylase in rapidly proliferating tissues. In addition, both agents demonstrate antiproliferative activity against human lymphoblastoid (Daudi) cells in culture. Treatment of log-phase Daudi cells with doses of 6 U/ml of IFN or 1 mM DFMO resulted in a 50% reduction of cell number 72 h after drug addition. Combination of IFN with DFMO against DAUDI cells using the isobologram method showed that the two demonstrate true antiproliferative synergy. Analysis of 2',5'-oligoadenylate synthetase (2,5A) activity in treated cells showed that both IFN alone and IFN/DFMO combination result in equivalent 2,5A induction (1800 mmol/mg/20 h) compared to control (300 mmol/mg/20 h). While 2,5A activity decreased by 50% at 48 h in cells after treatment with IFN alone, the IFN/DFMO combination remained elevated (1700 mmol/mg/20 h). Phosphodiesterase (PdE) activity in these cells showed no substantial changes with IFN, DFMO, or IFN/DFMO treatment over 72 h compared to control values. In contrast, the activity of the 68-kDa interferon induced protein kinase (PK) in IFN/DFMO-treated cells was 1.6-fold greater at 48 and 72 h than that found for IFN alone. These studies demonstrate that the synergistic antiproliferative activity of IFN/DFMO combination may be due, in part, to modification of the activity of IFN-inducible enzymes.
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PMID:Biochemical effects of human alpha interferon in combination with alpha-difluoromethylornithine on human lymphoblastoid (DAUDI) cells in culture. 165 71

Cyclosporine, but not its nonimmunosuppressive analog cyclosporine H (CsH), caused in a variety of hematopoietic cell types a growth arrest in the G0/G1 phase of the cell cycle. This arrest was associated with a significant reduction in the c-myc mRNA levels, which could be observed already 1 hr following CsA treatment. Similarity between the antiproliferative effects of CsA and IFN-alpha was observed. Thus, the IFN-alpha sensitive human B-lymphoblastoid cell line Daudi was also sensitive to CsA while an IFN-alpha resistant variant of Daudi cells was found to be resistant to CsA as well. Inhibition of protein synthesis with cycloheximide during IFN-alpha or CsA treatment blocked their ability to reduce the expression of c-myc. Depletion of protein kinase C (PKC) activity from cells by pretreatment of Daudi cells with phorbol.12-myristate 13-acetate (PMA) abolished the G0/G1 arrest induced by both CsA and IFN-alpha. Combinations of low concentrations of CsA and IFN-alpha had synergistic effects on cell-cycle distribution and on c-myc mRNA level, suggesting that CsA and IFN-alpha differ in some features of their antiproliferative action. This conclusion was supported by the observation that a CsA-resistant variant of Daudi cells was found to retain its sensitivity to IFN-alpha. In addition, reduction of ornithine decarboxylase mRNA expression was obtained with IFN-alpha but not with CsA. Taken together, our results suggest that CsA and IFN-alpha share some common element(s) in the pathways of their antiproliferative activity. The possible mechanisms of their antigrowth effects and the clinical significance of our findings are discussed.
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PMID:The antiproliferative effect of cyclosporine on hematopoietic and lymphoblastoid cell lines--common mechanistic elements with interferon-alpha. 204

Colony-stimulating factors (CSFs) stimulate the activation and steady-state mRNA accumulation of an important regulatory enzyme for macromolecular synthesis, ornithine decarboxylase (ODC). Cloned murine CSF-dependent cell lines exhibited a rapid activation of ODC enzyme activity, detectable within ten minutes of stimulations with either interleukin-3 (IL-3), GM-CSF, or G-CSF. This early phase of enzyme activation did not require early protein or mRNA synthesis. The subsequent protracted rise in ODC activity occurring four to six hours after CSF treatment was dependent on increases in steady-state ODC mRNA accumulation and de novo protein synthesis. CSF, therefore, modulates both posttranslational activation of preexisting ODC and stabilization and accumulation of ODC mRNA. Antiproliferative signals, such as cAMP or interferon-gamma (IFN-gamma), effectively inhibited the CSF-directed increase in steady-state ODC mRNA. Cotreatment of the murine NSF 60.8 cell line with IFN-gamma and GM-CSF decreased steady-state ODC mRNA greater than 80% as compared with GM-CSF-treated cells alone. IFN treatment did not cause any appreciable destabilization of mature ODC mRNA, suggesting that its major effect may be at the level of ODC mRNA transcription or posttranscriptional processing. These data indicate that the ODC gene-protein system is an important molecular locus of the effects of myeloid proliferative and antiproliferation signals.
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PMID:Myeloid growth factor(s) regulation of ornithine decarboxylase: effects of antiproliferative signals interferon-gamma and cAMP. 246 92

The present study analyzes the effect of murine IFN-gamma on DNA synthesis, ornithine decarboxylase activity and phosphorylation of pp60src of Rouse sarcoma virus transformed cells. When natural or recombinant IFN-gamma was added to quiescent SR-BALB or L1210 cells, stimulated with fetal calf serum, only the highest IFN-gamma concentrations (2000 U/ml) inhibited DNA synthesis of both tumor lines. By contrast, lower IFN-concentrations (20-200 U/ml) inhibited the DNA synthesis of L1210 but not of SR-BALB tumor cells. A similar pattern of inhibition was observed when ornithine decarboxylase activity was analyzed. Finally, when the levels of phosphorylation in SR-BALB cells were analyzed after IFN-gamma treatment, no difference with untreated controls was observed, even at the highest concentrations. These results suggest that SR-BALB tumor cells are insensitive to IFN-gamma and that src oncogene activity is not affected at IFN-concentrations inhibiting cell growth.
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PMID:Interferon-gamma inhibits cell replication, but not pp60src activity of RSV-transformed fibroblasts. 303 51

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and human leukocyte interferon (IFN-alpha) have synergistic anti-tumor activities in vivo in B 16 melanoma and in vitro against several human cancer cell lines. We have, therefore, carried out a phase I combination study with DFMO plus alpha interferon in the following manner: DFMO was maintained at a steady dose for the first four levels, 1.5 g/m2 every 6 hr. IFN-alpha was given in 100% increments ranging from 0.4 X 10(6)U/m2 to 3.2 X 10(6)U/m2 i.m. daily. At the fifth dose level both IFN-alpha and DFMO were raised by 100 and 50% respectively. From levels one through four the combination was well tolerated with no dose interruptions required because of G.I. toxicity or myelosuppression. However, at dose level 5, one-third of the patients required dose cessation and decrease due to nausea, vomiting and diarrhea. We conclude that for phase II studies the maximal tolerated dose is 3.2 million units of IFN-alpha/m2 and 1.5 g/m2 of DFMO every 6 hr. Of 12 patients with metastatic melanoma, 2 had partial remissions lasting 58+ and 36+ weeks. Two additional patients had minor responses lasting 29 and 32+ weeks. Minor responses were observed in a patient with colon carcinoma and a patient with renal carcinoma. The clinical activity of the combination is currently being pursued in a phase II study among patients with metastatic malignant melanoma.
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PMID:Difluoromethylornithine and leukocyte interferon: a phase I study in cancer patients. 309 71

Both mouse interferon-beta (MuIFN-beta) and the inhibitor of ornithine decarboxylase (ODC), alpha-difluoromethyl ornithine (DFMO), inhibited the differentiation of mouse 3T3-L1 fibroblasts into adipocytes in a dose-dependent manner. DFMO and MuIFN-beta added together to cultures that were induced to differentiate produced an additive anti-differentiation effect. In contrast to this additive cellular effect, DFMO reduced the antiviral activity of MuIFN-beta in both undifferentiated and differentiated cells; DFMO alone had no detectable effect on replication of encephalomyocarditis virus. Putrescine, the product of ornithine decarboxylation, when added to 3T3-L1 cultures (i) enhanced differentiation, (ii) reversed completely the inhibition of differentiation by DFMO, but (iii) had little effect on the antidifferentiation effect of MuIFN-beta. Polyamine content changed four-fold or less in cultures treated with 0.5 mM DFMO and less than two-fold in cultures treated with 100 IU/ml MuIFN-beta for seven days. Thus, it appears not only that MuIFN-beta and DFMO inhibit differentiation of 3T3-L1 cells by different mechanisms but also that the antiviral action of IFN does not involve the regulation of polyamine metabolism by ornithine decarboxylase.
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PMID:Inhibition of the differentiation of 3T3-L1 cells by interferon-beta and difluoromethyl ornithine. 314 Jun

Both mouse interferon-beta (MuIFN-beta) and the inhibitor of ornithine decarboxylase (ODC), alpha-difluoromethyl ornithine (DFMO), inhibited the differentiation of mouse 3T3-L1 fibroblasts into adipocytes in a dose-dependent manner. DFMO and MuIFN-beta added together to cultures that were induced to differentiate produced an additive anti-differentiation effect. In contrast to this additive cellular effect, DFMO reduced the antiviral activity of MuIFN-beta in both undifferentiated and differentiated cells; DFMO alone had no detectable effect on replication of encephalomyocarditis virus. Putrescine, the product of ornithine decarboxylation, when added to 3T3-L1 cultures (i) enhanced differentiation, (ii) reversed completely the inhibition of differentiation by DFMO, but (iii) had little effect on the anti-differentiation effect of MuIFN-beta. Polyamine content changed four-fold or less in cultures treated with 0.5 mM DFMO and less than two-fold in cultures treated with 100 IU/ml MuIFN-beta for seven days. Thus, it appears not only that MuIFN-beta and DFMO inhibit differentiation of 3T3-L1 cells by different mechanisms but also that the antiviral action of IFN does not involve the regulation of polyamine metabolism by ornithine decarboxylase.
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PMID:Inhibition of the differentiation of 3T3-L1 cells by interferon-beta and difluoromethyl ornithine. 314 19

The purpose of this study was to determine whether all commercially available forms of interferon alfa (INF alpha) have the same inhibitory effect on hepatic regeneration and whether this inhibitory effect can be prevented by putrescine, a hepatic growth promotor. Adult male Sprague-Dawley rats (n = 92) received either IFN alpha-2a, 2b, n1, or saline, 0 and 18 hours after partial hepatectomy (PHx) or 16 hours before PHx. A subgroup of 29 rats being treated with IFn alpha-2a or saline also received putrescine (5, 50, or 500 mg/kg) 16 hours before PHx. Hepatic regeneration was documented by determining [3H]-thymidine incorporation into hepatic DNA (DNA synthesis), hepatic putrescine levels, and, in selected cases, ornithine decarboxylase (ODC) activity at 24 hours after PHx. The results of the study showed that hepatic regeneration was unaffected when IFN alpha was administered 0 and 18 hours after PHx. When administered at -16 hours, only IFN alpha-2a significantly inhibited DNA synthesis and was associated with decreased hepatic putrescine levels. Inhibition was dose-dependent in that a 10-fold increase in IFN alpha-2a caused a further decrease in both DNA synthesis and hepatic putrescine levels. At the higher dose, IFN alpha-2b and n1 also inhibited DNA synthesis and lowered hepatic putrescine levels and ODC activity. Exogenous putrescine (5 and 50 mg/kg) restored hepatic regenerative activity to normal but was toxic at high concentrations (500 mg/kg). These data indicate that not all commercially available forms of IFN alpha inhibit hepatic regeneration in the rat to the same extent.
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PMID:The differential effects of three forms of interferon alfa on hepatic regeneration after partial hepatectomy in the rat. 765 96


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