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)

Difluoromethylornithine (DFMO) is a nonreversible inhibitor of ornithine decarboxylase (ODC), the initial rate-limiting enzyme in the polyamine biosynthetic pathway. When HL60 leukemic cells were incubated in the presence of concentrations of DFMO from 0.05 mM to 5 mM, there was a concentration-dependent inhibition of ODC activity apparent within 24 h. Likewise, cellular polyamine levels were reduced by the presence of DFMO in a concentration-dependent manner after 4 days. The growth of cells incubated with 0.5 mM or greater was inhibited after 3-4 cell doublings. When the concentration of DFMO was less than 0.5 mM, growth was not inhibited. Methylglyoxal-bis(guanylhydrazone) (MGBG) uptake was enhanced in cells treated with concentrations of 0.05-0.5 mM DFMO, but not enhanced in cells treated with DFMO concentrations of 1 mM or greater. DFMO-induced cellular polyamine depletion does enhance MGBG uptake into HL60 cells, but treatment with high concentrations of DFMO, which deplete polyamines to the extent that growth is inhibited, negate this effect.
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PMID:Difluoromethylornithine enhances the uptake of methylglyoxal-bis(guanylhydrazone) prior to inhibiting leukemic cell proliferation. 310 68

Polyamines (putrescine, spermidine and spermine) are considered to act as intracellular second messengers by increasing Ca++ influx and mobilizing intracellular calcium. On the other hand, intracellular Ca++ increase is the common final step of the mechanism of action of many inotropic agents. To discover whether the functional integrity of the cardiac ornithine decarboxylase (ODC)/polyamine system is necessary to cope with a stimulated inotropism, we studied the effect of ouabain, noradrenaline, and calcium on ventricle strips obtained from rats treated with polyamine synthesis inhibitors. The combined administration of methylglioxal bis (guanylhydrazone) (MGBG) (single i.p. injection of 50 mgkg-1) and of alpha-di fluoromethylornithine (DFMO) (100 mgkg-1 every 12 h for 7 consecutive days) caused a 62.5% inhibition of ventricular ODC activity, and a significant decrease of the ventricular content of putrescine and spermidine (-59.5%, and -40.1%, respectively). While the basal isometric tension developed by ventricle strips obtained from rats treated with MGBG+DFMO was similar to that developed by ventricle strips from controls, the response to ouabain (1 microM), noradrenaline (10 microM), or Ca++ (3.6 mM) was significantly reduced. It cannot be excluded that effects of MGBG unrelated to the inhibition of polyamine synthesis may have also concurred in part to influence the effect of ouabain, Ca++ and noradrenaline adversely. However, the present results seem to indicate that the heart response to inotropic agents requires an efficient ODC/polyamine system, polyamines probably being involved in calcium ion movements or affecting the Ca++ sensitivity of contractile proteins.
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PMID:Treatment with polyamine synthesis inhibitors reduces the positive inotropic effect of ouabain, noradrenaline and calcium. 313 85

The antitumor and antimetastatic effects of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, combined with an inhibitor of S-adenosylmethionine decarboxylase, either methylglyoxal bis(guanylhydrazone) (MGBG) or ethylglyoxal bis(guanylhydrazone) (EGBG), were studied in mice bearing P388 leukemia or Lewis lung carcinoma. Although EGBG is a more specific inhibitor of polyamine biosynthesis than the widely used MGBG, the antitumor effect of the DFMO-EGBG combination on P388 leukemia-bearing mice was less than that of the DFMO-MGBG combination. The prolongation of survival time by the DFMO(1000 mg/kg)-MGBG(25 mg/kg) combination was 2.65-fold, while that of the DFMO(1000 mg/kg)-EGBG(50 mg/kg) combination was 1.34-fold. When mice were fed a polyamine-deficient diet, stronger antitumor effects were exerted; the prolongation of survival time by the DFMO-MGBG and the DFMO-EGBG combinations was 2.89-fold and 2.03-fold, respectively. The antitumor effect of combined use of the two polyamine antimetabolites with mice on normal and polyamine-deficient diets correlated with a decrease of polyamine charge contents in the tumor cells. The above in vivo results were confirmed clearly in the KB cell culture system. The antimetastatic activity of DFMO on Lewis lung carcinoma-bearing mice was strengthened by the addition of MGBG or EGBG. The antimetastatic activity of the DFMO-MGBG or DFMO-EGBG combination did not parallel the polyamine charge contents in the primary tumor and blood.
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PMID:Combined use of alpha-difluoromethylornithine and an inhibitor of S-adenosylmethionine decarboxylase in mice bearing P388 leukemia or Lewis lung carcinoma. 313 38

Diethylglyoxal bis(guanylhydrazone) (DEGBG), a novel analog of the antileukemic agent methylglyoxal bis(guanylhydrazone) (MGBG) was synthesized. It was found to be the most powerful inhibitor of yeast S-adenosylmethionine decarboxylase (AdoMetDC) so far studied (Ki approx. 9 nM). This property, together with the finding that the compound is a weaker inhibitor of intestinal diamine oxidase than are MGBG and its glyoxal, ethylglyoxal and ethylmethylglyoxal analogs, makes the compound a promising candidate as a polyamine antimetabolite for chemotherapy studies. DEGBG was also found to potentiate the antiproliferative effect of the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine against mouse L1210 leukemia cells in vitro. DEGBG increased several-fold the intracellular putrescine concentration of cultured L1210 cells, just as MGBG and its ethylglyoxal analog are known to do. The results strongly suggest that DEGBG is worth further studies. Combined with previous studies, they also made possible the construction of some empirical rules concerning the structure-activity relationships of bis(guanylhydrazone) type inhibitors of AdoMetDC. The identity of DEGBG was confirmed by a single-crystal X-ray analysis and by 1H- and 13C-NMR spectroscopy. It consisted of the same isomer as MGBG and several of its analogs are known to consist of.
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PMID:Diethylglyoxal bis(guanylhydrazone): a novel highly potent inhibitor of S-adenosylmethionine decarboxylase with promising properties for potential chemotherapeutic use. 313 21

We have reported that 1-alpha,25-dihydroxyvitamin D3 [1-alpha,25-(OH)2D3] directly induces fusion of mouse alveolar macrophages at a very high rate (circa 70-80%) by a mechanism involving protein synthesis (Proc. Natl. Acad. Sci. USA 80:5583, 1983; FEBS Letters 174:61, 1984). While examining further the mechanism of the 1-alpha,25-(OH)2D3-induced fusion of macrophages, we found that polyamines are involved in this mechanism. Mouse alveolar macrophages incubated with 12 nM 1-alpha,25-(OH)2D3 began to fuse at 36 h and the fusion rate increased linearly up to 60 h. Addition of as much as 0.05-5 mM alpha-difluoromethylornithine (alpha-DFMO), a specific inhibitor of ornithine decarboxylase, did not inhibit fusion appreciably, but addition of 0.05-5 microM methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosylmethionine decarboxylase, strikingly inhibited fusion. When macrophages were treated with both 12 nM 1-alpha,25-(OH)2D3 and 5 microM MGBG for the first 12 h and incubated further for 60 h in fresh medium containing 1-alpha,25-(OH)2D3, fusion was significantly inhibited, suggesting that the 1-alpha,25-(OH)2D3-induced synthesis of polyamines precedes fusion. The inhibition by MGBG of the 1-alpha,25-(OH)2D3-induced fusion was restored completely by adding 1 microM spermidine or spermine or 100 microM putrescine. None of the polyamines alone induced fusion. MGBG suppressed the 1-alpha,25-(OH)2D3-induced incorporation of [3H]-leucine into the trichloroacetic acid-insoluble fraction in macrophages, but its inhibitory effect was restored completely by adding 1 microM spermidine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polyamines are involved in the 1-alpha,25-dihydroxyvitamin D3-induced fusion of mouse alveolar macrophages. 314 Jun 3

Mitoguazone (methylglyoxal-bis(guanyl-hydrazone), MGBG) was studied by its first-pass mechanism in both cancer patients and experimental cancer models. It appears from the study that 90% of MGBG is cleared from the plasma within minutes. 24-h recovery in the urine, however, did not exceed 16% so that 84% of the drug seems to be bound to subcellular compartments. Tissue levels of MGBG in the normal prostate ranged higher than in experimental prostate cancer type 3327 M/G, i.e. enhanced clearance from cancer tissues: polyamine biosynthetic enzymes ornithine decarboxylase as well as S-adenosylmethionine decarboxylase are contrarily affected by MGBG.
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PMID:Some aspects of clearance of mitoguazone in cancer patients and experimental cancer models. 351 31

We have studied the effect of methylglyoxal-bis (guanylhydrazone) (MGBG) and novobiocin on the accumulation of specific mRNAs in serum-stimulated ts13 cells (a temperature-sensitive mutant of the BHK cell line). The RNAs studied included: c-myc, v-ras, ornithine decarboxylase, beta-actin, histone H3, and those represented by clones p2F1 and p1B6 (Hirschhorn et al., Proc. Natl, Acad. Sci. USA, 81:6004, 1984) All these RNAs accumulated at higher levels when quiescent cells were serum stimulated for 16 h. Both MGBG (25 micronM and 100 micronM) and novobiocin (200 micrograms/ml) effectively prevented the transition from G0 to S phase. We found that 100 microM MGBG induced an overaccumulation of c-myc RNA while H3 RNA was decreased, and the steady-state levels of all other RNAs were the same as in cells stimulated without the drug. Novobiocin prevented the serum-induced increase in the amount of all RNAs, which remained at the same levels as in quiescent cells, with the exception of c-myc, which again accumulated at a higher level in drug-treated cells than in serum-stimulated untreated cells. The possible significance of these results is discussed.
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PMID:Selective increase of c-myc mRNA levels by methylglyoxal-bis (guanylhydrazone) and novobiocin in serum-stimulated fibroblasts. 352 75

Ornithine decarboxylase (ODC) was induced in the liver, lung and brain of the mouse injected intraperitoneally with 12-O-tetradecanoylphorbol 13-acetate (TPA), showing maximal enzyme activity four hours after the injection. The increase of ODC activity was due to the enhanced syntheses of mRNA and protein. The induction of ODC activity by TPA was specifically blocked by methylglyoxal bis(butylamidinohydrazone) (MGBB), a competitive inhibitor of ODC and S-adenosylmethionine decarboxylase, but not by the analog methylglyoxal bis(guanylhydrazone) (MGBG).
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PMID:Induction of ornithine decarboxylase activity in mouse tissues by phorbol ester is effectively blocked by methylglyoxal bis(butylamidinohydrazone). 357 40

The activities of ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SAT) were increased by the addition of S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor methylglyoxal bis(guanylhydrazone) (MGBG) in cultured human erythroid leukemia K 562 cells. ODC activity began to increase 4 hr after the addition of the drug and attained a maximum at 12 hr. The increase of SAT activity lagged behind that of ODC activity. The increases of both ODC and SAT activities produced by MGBG were blocked by treatment with cycloheximide, suggesting that the increase of enzyme activity resulted from the synthesis of new enzyme proteins. The putrescine content in cells treated with MGBG increased markedly, whereas the levels of spermidine and spermine were depressed lower. On the other hand, methylglyoxal bis(butylamidinohydrazone) (MGBB), a derivative of MGBG inhibiting AdoMetDC effectively, did not induce ODC or SAT activities.
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PMID:Ornithine decarboxylase and spermidine/spermine N1-acetyltransferase are induced in K562 cells by S-adenosylmethionine decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) but not by analogous methylglyoxal bis(butylamidinohydrazone). 377 24

Uptake characteristics and growth-inhibitory effects of methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were investigated in 9L rat brain tumor cells and in V79 hamster lung cells. Proliferation of 9L cells was only slightly inhibited by treatment with 40 microM MGBG alone, but when used in combination with 0.5 mM alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, proliferation was much more effectively inhibited. The intracellular concentration of MGBG was approximately 2-fold higher 4 days after cells were treated with both DFMO and MGBG, either simultaneously or when MGBG was added after a 48-hr DFMO pretreatment, than that in cells treated with MGBG alone. Polyamine levels in DFMO- and MGBG-treated cells correlated with the antiproliferative effects of the drugs. Used either alone or in combination with 1 mM DFMO, 0.5 microM MGBG inhibited the growth of and eventually killed V79 cells. Simultaneous or sequential treatment with DFMO and MGBG increased intracellular concentrations of MGBG at 4 days by 2- and 3-fold, respectively, compared to treatment with MGBG alone. Intracellular polyamine levels did not correlate with the antiproliferative effect of the two drugs in V79 cells. In both cell lines, polyamines and MGBG share a common transport system. The net transport of polyamines and MGBG was more temperature dependent and up to 10-fold more active in V79 cells than in 9L cells. The Km and Vmax values for spermidine and MGBG measured 10 sec after addition (initial permeation) were not affected by DFMO pretreatment in either cell line. However, 1 hr after administration, the Vmax values for spermidine and MGBG uptake were doubled in V79 cells pretreated for 48 hr with DFMO; no significant change occurred in 9L cells. Mitochondrial function, assessed by pyruvate oxidation, was substantially impaired by MGBG in V79 cells but not in 9L cells when the intracellular concentrations of MGBG were equal in each cell line. Pretreatment with DFMO did not increase MGBG-induced inhibition of pyruvate oxidation in V79 cells. These results show that, compared with V79 cells, the decreased sensitivity of 9L cells to MGBG may be related to decreased intracellular MGBG accumulation but not to cellular permeation such as carrier transport. Results of measurements of both polyamine levels and mitochondrial function indicate that V79 cells may be more susceptible to nonpolyamine-dependent effects of MGBG than are 9L cells.
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PMID:Modification of uptake and antiproliferative effect of methylglyoxal bis(guanylhydrazone) by treatment with alpha-difluoromethylornithine in rodent cell lines with different sensitivities to methylglyoxal bis(guanylhydrazone). 391 47


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