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)

We previously have shown that urine components capable of stimulating ornithine decarboxylase activity of urothelium can enhance rat urinary bladder carcinogenesis, and that alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses carcinogen-initiated rat urinary bladder carcinogenesis. The present investigation was conducted to determine whether DFMO's suppressive effect is stage specific during carcinogenesis and whether the suppressive effect lasts with its continued use. Following initiation with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine in drinking water for 6 wk, male Fischer 344 rats initially weighing 125 to 150 g were randomly divided into two groups, the first receiving 0.2% DFMO in drinking water ad libitum and the second receiving tap water only. Groups of animals were killed at regular intervals until the completion of the experiment at 75 wk. The effect of DFMO was evaluated by monitoring the incidence of tumors, the mean number of tumors per rat, the mean volume of individual tumors, and the mean total tumor volume per rat. The results showed that continuous treatment with DFMO significantly reduced tumor formation until 60 wk (P less than 0.017). The effect was only of borderline significance (0.017 less than P less than 0.035) at 75 wk. Discontinuation of DFMO treatment at 40 wk resulted in the loss of protective effect in all comparisons except for the borderline effect on the tumor number and total tumor volume per rat. DFMO had no significant effect on the incidence or development of preneoplastic early lesions. Mucosal polyamine (spermidine and spermine) levels were reduced and correlated well with the reduction in tumor growth, suggesting that the reduction in tumor growth rate by DFMO may be due to its ability to reduce polyamine levels in urothelium. There were no side effects attributable to DFMO treatment. DFMO may be a useful chemopreventive agent to retard the recurrence of human superficial bladder cancer.
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PMID:Inhibitory action of alpha-difluoromethylornithine on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat urinary bladder carcinogenesis. 250 87

The glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has been shown to inhibit the growth of certain cancers. alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. DFMO has been shown to inhibit cancer growth in a number of models. The present study was designed to investigate the effects of 2-DG alone and combined with DFMO on MC-26 mouse colon adenocarcinoma tumors growing in vivo. Twenty-eight male Balb/c mice were inoculated with 250,000 MC-26 cells, and then randomized into four groups of 7 each: group I served as control; group II received DFMO (3% in drinking water); group III received 2-DG (500 mg/kg/d IP); group IV received combination of 2-DG and DFMO. Treatment began 5 days after tumor cell inoculation. MC-26 tumor area was reduced 73% by DFMO compared to a 24% reduction caused by 2-DG. The tumor weight was reduced 80% by DFMO and 52% by 2-DG. The tumor contents of DNA, RNA, and protein were significantly reduced by DFMO but not 2-DG. The tumor concentration of the polyamines putrescine and spermidine were reduced by DFMO alone or combined with 2-DG while spermine levels remained unchanged. 2-DG alone did not alter polyamine levels. These results indicate that both 2-DG and DFMO, when added as single agents, inhibit tumor growth. However, the addition of 2-DG to the DFMO regimen inhibited the antitumor effects of DFMO. Survival studies performed on MC-26 cells in vitro corroborated the antagonisms between DFMO and 2-DG that were shown in vivo.
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PMID:2-Deoxy-D-glucose inhibits the antitumor effects of alpha-difluoromethylornithine on the growth of colon cancer in vivo. 250 71

DL-alpha-Difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor of mammalian ornithine decarboxylase. DFMO, when administered in drinking water, precludes increases in the levels of intracellular putrescine and spermidine and also inhibits the induction of skin, breast, colon, urinary bladder, and intestinal cancers in experimental animal models. DFMO may be a useful drug for cancer prevention in humans; however, long-term medication with higher doses (9 g/m2/day) of DFMO has resulted in several toxic side effects such as thrombocytopenia and reversible ototoxicity. Smaller doses (less than 1 g/m2/day), selected by our in vitro human skin punch biopsy assay, may be given for a longer period without appreciable toxicity. Further evaluation in human cancer prevention trials is indicated.
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PMID:The enzyme-activated irreversible inhibitor of ornithine decarboxylase, DL-alpha-difluoromethylornithine: a chemopreventive agent. 251 33

Polyamines are compounds required for initiation of rapid cellular growth and differentiation in many cell types. Ornithine decarboxylase is the rate limiting enzyme in polyamine synthesis. Fasting and refeeding regulates the activity of ornithine decarboxylase and polyamine content in the intestinal tract. We tested the hypothesis that polyamines regulate cell growth via the Na+/H+ exchanger which is believed to be intimately involved in cell growth. Ileal Na+/H+ activity was therefore examined in control, fasted, refed fasted, and in rats given the specific inhibitor of ornithine decarboxylase alpha-difluoromethylornithine. A well-validated ileal brush border membrane vesicles for the study of Na+/H+ exchange activity was utilized. Fasting markedly decreased while refeeding stimulated Na+/H+ exchange activity at all times studied (P less than 0.05-0.001). Maximal uptake of Na+ at 5 min was 3.12 +/- 0.05, 2.5 +/- 0.05 and 2.22 +/- 0.05 nmol/mg protein in refed, control and fasted rats respectively. Kinetics of amiloride sensitive Na+/H+ exchanger showed a Vmax of 17.1 +/- 3.5, 8.0 +/- 0.64 and 4.7 +/- 1.1 nmol/mg protein per 5 s in refed fasted, control and fasted rats respectively Km values were not significantly different between the groups studied. 2% alpha-difluoromethylornithine given in the drinking water abolished the stimulation in Na+/H+ exchange activity in refed fasted rats. These results suggest a close relationship between polyamines and Na+/H+ activity in the intestinal mucosa of rats.
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PMID:Effect of dietary polyamines and alpha-difluoromethylornithine on regulation of intestinal Na+/H+ exchanger. 256 Apr 78

The administration of theophylline (120 mg/kg.day, 14 wk) to the drinking water of female BALB/c mice after treatment with 1,2-dimethylhydrazine (DMH) (30 mg/kg.sc, 1/wk, 14 wk) resulted in both an increase in number of colon carcinoma and increases in ornithine decarboxylase (ODC) activities and polyamine (PA) levels in colon tissue. This increase in number of colon carcinoma was about 3-fold to mice receiving same amount of DMH and drinking water without theophylline. ODC activities (pmoles 14CO2/hr/mg prot, mean +/- SD) in colon tissue were 122 +/- 10.6 (n = 6) in DMH with theophylline group, 28.3 +/- 2.13 (n = 8) in DMH alone group, 21.3 +/- 1.67 (n = 6) in control group respectively. Putrescine and spermidine levels (nmoles/g, mean +/- SD) were 31.0 +/- 10.5, 527 +/- 86.6 (n = 11) in DMH with theophylline group, 24.0 +/- 11.4, 464 +/- 129 (n = 11) in control group respectively. Thus with marked increase of ODC activities and slight increase of PA levels, theophylline has shown to significantly enhance the promoting phase of carcinogenic process with DMH.
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PMID:[The influence of theophylline on polyamine metabolism and colonic carcinogenesis induced by 1.2-dimethylhydrazine in mice]. 259 8

The effect of cyclosporine A (CsA) and alpha-difluoromethylornithine (DFMO) on the camostate-induced increase in pancreatic ornithine decarboxylase (ODC) activity and polyamine biosynthesis has been studied in vivo. Six hours after application of the synthetic trypsin inhibitor camostate (200 mg/kg b wt orally) pancreatic ODC activity increased about 140-fold and putrescine concentration about ninefold. CsA inhibited the elevation of both parameters in a dose-dependent manner. CsA pretreatment for 3 d with doses of 7.5, 10.0, and 12.5 mg/kg b wt orally once a day and consecutive CsA blood levels 24 h after the last CsA application of 751 +/- 62, 968 +/- 70, and 1,395 +/- 79 ng/mL, respectively, resulted in a complete inhibition of the camostate-stimulated increase in pancreatic ODC activity and putrescine concentration in vivo. DFMO (2% in drinking water and additionally 300 mg/kg b wt intraperitoneally at 8 AM, 12 noon, and 4 PM) inhibited the increase in both, ODC activity, and putrescine, significantly in an equipotent degree as 2.5 mg CsA/kg b wt, whereas higher doses of CsA proved to be more effective than DFMO in the chosen subtoxic dose. In all cases, no significant changes in pancreatic spermidine and spermine concentration, DNA and protein content, or pancreatic and body weight were observed. It is concluded that CsA in doses used for immunosuppression in clinical practice is a very potent and more effective inhibitor of ODC activity and polyamine synthesis in vivo than DFMO. This ODC inhibitory effect of CsA is a further detail to elucidate the up to now incompletely understood mechanisms of action of this immunosuppressive agent.
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PMID:Dose-dependent inhibition by cyclosporine A of the induction of pancreatic ornithine decarboxylase (ODC) in rats. 260 Apr 52

Tetrahymena thermophila cells grown in a synthetic nutrient medium for 9 h removed 97% of the free L-arginine but less than 50% of any of the other essential amino acids. The major portion of the arginine was degraded rapidly (76-92%) whereas 5-15% was conserved as intact and only 2.5-10% were incorporated into protein. However, if bovine serum albumin (BSA) was present in the medium as a macromolecular arginine source the incorporation of free arginine into protein was reduced to less than 1% but the degraded fraction was increased. Apparently, the uptake mode of arginine determines its fate: arginine taken up by phagocytosis is bound for protein biosynthesis, arginine taken up by membrane receptors is chanelled to degradation. Media without arginine did not support growth of Tetrahymena. Citrulline and ornithine, the precursors of arginine biosynthesis in yeast and vertebrates, were not able to substitute for arginine. Pronounced morphological changes, e.g. greatly reduced ribosome content, were observed in Tetrahymena cells after 24 h of arginine starvation in otherwise complete medium, but not in cells starved in water, salt solution, or buffer. Thus, arginine is an essential nutrient component for Tetrahymena and the rapid degradation of this compound involving the enzymes arginine deiminase (ADI) and citrulline hydrolase (CH) might be of regulatory importance for the unicellular, as it is the case with acetylcholine and catecholamines in mammalian organisms. Since the product of these enzymes, L-ornithine, is the substrate for the regulatory key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), the effects of the presence of absence of arginine on the activities of each particular enzyme of the pathway were studied, including ODC and the enzyme ornithine-oxo-acid aminotransferase (O delta T), which is a competitor of ODC for the common substrate. The arginine-degradative pathway was stimulated by extracellular free but not by peptide-bound arginine and was modulated by extracellular protein which induced phagocytosis; O delta T was stimulated with a time lag. The stimulation of ODC was in a reciprocal relation to the arginine concentration and enhanced by phagocytosis and previous arginine starvation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Stimulation of growth and polyamine biosynthesis of the ciliated protozoan Tetrahymena thermophila. Regulation by L-arginine. 261 Sep 29

The present study has investigated the question of whether or not hydrocortisone as a gene regulator plays a role in the expression of carcinogenic and cocarcinogenic actions of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and NaCl at the gastric epithelium. The interaction of local hydrocortisone, MNNG and NaCl was studied in vitro and in vivo using Swiss/ICR mice of both sexes. MNNG inhibited specific hydrocortisone binding with the cytoplasmic receptor from the glandular stomach of mouse. The intake of both excess NaCl and MNNG induced an increase in hydrocortisone turnover in the glandular stomach of mouse. Likewise, administration of either excess NaCl or MNNG increased the activity of ornithine decarboxylase in the glandular stomach of mouse. Long-term use of a salt-rich diet and MNNG drink induced an irreversible reduction in water consumption without affecting NaCl consumption, a dissociation of the hydrocortisone effect. The aforementioned MNNG effect on water turnover was more marked in female than in male mice. It is suggested that NaCl and MNNG produce a state of corticosteroid stimulation and androgen depression at the glandular stomach epithelium of mouse--a reproduction of the hormonal markers of gastric cancer.
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PMID:Interaction between N-methyl-N'-nitro-N-nitrosoguanidine and 2 steroid hormones in the glandular stomach of mouse. I. Acceleration of hydrocortisone turnover by use of a salt-rich diet and the carcinogen. 277 56

Two in vivo and one in vitro studies were performed to evaluate the chemoprotective role of calcium during the early period of azoxymethane (AOM) induction. In the first set of experiments, groups of male Fischer 344 rats were s.c. injected with either AOM (20 mg/kg) or water (controls) and sacrificed immediately (0 time), and 1, 3, 5, and 7 days postinjection. In the second set of experiments, animals were injected with the same dose of AOM and subsequently pair-fed with rat chow containing either calcium carbonate or diet devoid of added calcium. The amount of calcium consumed was calculated to be 250 mg/kg b.w. In both experiments, colonic mucosa was assayed for ornithine decarboxylase (ODC). In addition, tyrosine kinase (Tyr-k) activity as well as tyrosine specific phosphorylation of membrane proteins were determined. Results revealed that maximal stimulation by AOM of ODC and Tyr-k activity occurred 5 days postinjection. This stimulation was significantly suppressed by calcium. AOM also produced an increase in the rate of tyrosine specific phosphorylation of two distinct colonic mucosal membrane proteins with Mr of 57,000 and 59,000. Again, dietary calcium suppressed the stimulation. In the third set of experiments, organ culture was utilized. Methylazoxymethanol, the active metabolite of AOM, was used instead of AOM in this part of the study. Four hour exposure of mucosal explants to methylazoxymethanol (1 microgram/ml) resulted in a significant (20-30%) increase in ODC and Tyr-k activity when compared to controls. Addition of either CaCl2 (2 mumol/ml) or difluoromethylornithine (2 nmol/ml) the irreversible inhibitor of ODC, significantly suppressed the methylazoxymethanol-induced activity of both ODC and Tyr-k. We conclude that calcium may have a chemoprotective role and tyrosine kinases may have a regulatory role in the early stages of AOM induction of colon cancer.
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PMID:Attenuation of azoxymethane-induced colonic mucosal ornithine decarboxylase and tyrosine kinase activity by calcium in rats. 279 Aug 2

To evaluate the role of polyamine biosynthesis in myocardial growth, the activity of ornithine decarboxylase (ODC) and the levels of the polyamines, spermidine, spermine, and putrescine, were measured in the hearts of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats between birth and 30 wk of age and in 30-wk-old rats after 6 wk treatment with either minoxidil (0.08 mg/ml) or methyldopa (5 mg/ml drinking water). ODC activity was initially high in the developing heart (150 pmol X mg protein-1 X 30 min-1) and decreased with age. In the SHR after 4 wk of age, spermidine content was consistently raised in both ventricles compared with the WKY rats. Spermine was reduced in the left ventricle of the SHR, resulting in high spermidine-to-spermine ratios characteristic of rapidly growing systems. Ventricular ODC activity and putrescine levels were also slightly but less consistently elevated in the ventricles of the SHR compared with respective WKY rats. Minoxidil treatment increased heart weight and left ventricular spermidine and spermine content in both SHR and WKY rats. Methyldopa also caused a significant increase in left ventricular spermidine content despite a marked reduction in ventricular mass. Thus ventricular hypertrophy in SHR is accompanied by an enhanced synthesis and accumulation of spermidine. The fact that myocardial spermidine content increased during methyldopa treatment, which reduced the myocardial mass, suggests that regression of ventricular hypertrophy can occur independently of changes in polyamine content.
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PMID:Altered cardiac polyamine biosynthesis in spontaneously hypertensive rats. 295 95


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