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PubMed1995

Characterization of the effects of polyamines on the modulation of the N-methyl-D-aspartate receptor by glycine.

We have investigated the effects of polyamine agonists and antagonists on the modulation of the N-methyl-D- aspartate receptor by glycine using a [3H]dizocilpine ([3H]MK801) binding assay. We monitored the non-equilibrium binding of [3H]dizocilipine in the presence of 5,7-dichlorokynurenate to preclude occupation of the glycine site by endogenous glycine. Using this assay, spermine and spermidine increased both the affinity and the maximum effect of glycine. Similar effects are produced by other polyamine agonists including 1,5-diethylaminopiperidine, neomycin and Ca2+. These actions are reversed by the polyamine glycine produced by polyamine agonists appears to be due to an increase in the equilibrium affinity of [3H]dizocilpine, and cannot therefore be attributed solely to modulation of glycine binding. Interestingly, 1,5-diethylaminopiperidine increases the maximum effect of glycine to a greater extent than it alters glycine affinity, suggesting that the two effects may be mediated by different sites or mechanisms. These studies will help to define the role of the glycine site in the modulation of the N-methyl-D-aspartate receptor by polyamines.

Animals↗
PubMed1985

1H, 13C, and 31P nuclear magnetic resonance studies of cowpea mosaic virus: detection and exchange of polyamines and dynamics of the RNA.

1H and 13C NMR studies on cowpea mosaic virus (CpMV) revealed that polyamines are present in the middle (M) and upper bottom (BU) components obtained by CsCl density gradient centrifugation but not in the top (T) component; the lower bottom (BL) component contains trace amounts of polyamine. Dialysis of the BL component against spermidine led to incorporation of spermidine which gave rise to NMR peaks very similar to those observed with the natural M and BU components. NMR results conclusively demonstrate that polyamines in the M and BU components of CpMV are exchangeable with cesium ions and the exchange process is pH dependent. They also provide experimental support for the hypothesis that the BU to BL conversion results from the displacement of polyamines and possibly other natural counter ions of the RNA by cesium ions [G. Bruening, (1977), In "Comprehensive Virology" (H. Fraenkel-Conrat and R. R. Wagner, eds.), Vol. 11, pp. 55-141. Plenum, New York]. No sharp peaks, attributable to mobile amino acid side chains, were seen in spectra of an intact CpMV particle or its empty protein shell (T component). 31P NMR spin-lattice relaxation time and nuclear Overhauser effect parameters, which are sensitive to high-frequency motions, suggest that the RNA and, when present, the bound polyamine undergo internal motions with correlation times in the nanosecond range.

Carbon Isotopes↗
PubMed1983

Suppression of ribosomal gene expression in oocytes and nurse cells of a polychaete as a result of polyamine synthesis inhibition.

The role of the polyamines in ribosomal gene expression was evaluated in the polychaete Ophryotrocha labronica by analyzing the effects of polyamine synthesis inhibition on RNA synthesis during oogenesis, a period characterized by intense nucleolar activity. At various stages of oogenesis adult polychaete females were blocked in their polyamine synthesis by the addition of 10 mM DL-alpha-difluoromethylornithine (DFMO) to the sea water in which they were cultivated. To monitor RNA synthesis during DFMO treatment the animals were pulse-labeled with [5-3H]uridine and processed for autoradiography. Light and electron microscope autoradiographs demonstrate that DFMO treatment suppresses incorporation of label into nucleolar RNA (rRNA) both in the oocytes and their associated nurse cells. The ultrastructural appearance of both cell types reveals interference with nucleolar and ribosomal activity; the endoplasmic reticulum is deprived of ribosomes, and the production of protein granules (vitellogenesis) is reduced. The high specificity of DFMO for polyamine synthesis and the fact that the effects of DFMO were counteracted by addition of a low concentration (10 microM) of putrescine shows that the observed interference with ribosomal gene expression is indeed due to polyamine deficiency.

Age Factors↗
PubMedDate not supplied

Inhibition of ornithine decarboxylase activity decreases polyamines and suppresses DNA synthesis in human colonic lamina propria lymphocytes.

Ornithine decarboxylase (ODC) and the polyamines are essential for cell proliferation in a variety of cells including lymphocytes. In this study, we investigated the potential role of ODC and polyamines in human colonic lamina propria lymphocytes (LPL) compared to peripheral blood lymphocytes (PBL). Our results show that con A stimulation of LPL and PBL was associated with marked increases in ODC and polyamines. The specific inhibitor of ODC, alpha-difluoromethylornithine (DFMO), resulted in a complete inhibition of ODC activity and depletion of putrescine, spermidine and spermine levels. DFMO also suppressed DNA synthesis of LPL and PBL by up to 48% and 62% respectively. This antiproliferative effect was reversed by adding back the polyamines putrescine (1 mM), spermidine (10 microM) or spermine (10 microM) to the culture medium. We conclude that ODC and the polyamines are important for human LPL proliferation, and hence may play a role in human mucosal immune function.

Aged↗
PubMed1989

Determination of polyamines by precolumn derivatization with 9-fluorenylmethyl chloroformate and reverse-phase high-performance liquid chromatography.

A high-performance liquid chromatography (HPLC) method for the determination of picomole levels of polyamines (putrescine, spermidine, and spermine) is described. Amino groups in polyamines react with 9-fluorenylmethyl chloroformate (FMOC) to form stable and highly fluorescent derivatives which can be separated and quantitatively estimated by HPLC in about 12 min. The mean relative elution times (n = 14) for putrescine, spermidine and spermine are 4.21 +/- 0.02, 10.09 +/- 0.02 and 11.19 +/- 0.04 min, respectively. The method has been applied to determine polyamine concentration in rat dorsal root ganglia (DRG) without interference with endogenous amino acids. Polyamine content of individual rat DRG has been calculated and the values are as follows: putrescine, 36.8 +/- 2.01, spermidine, 1652 +/- 131.0 and spermine 388.5 +/- 38.4 pmol/DRG. Information on polyamine concentrations in DRG may be useful in understanding the mechanism of action of toxic chemicals on nervous system.

Animals↗
PubMed1988

Early polyamine treatment enhances survival of sympathetic neurons after postnatal axonal injury or immunosympathectomy.

We have recently demonstrated that following injury of their axon, sympathetic neurons of the rat superior cervical ganglion become dependent on polyamine synthesis for their survival. In addition we have observed that the treatment of newborn rats with biogenic polyamines can prevent the naturally occurring reduction in the number of neurons in the ganglion. In the present study groups of newborn rats were subjected to either postganglionic nerve crush (axotomy) or to treatment with antiserum to nerve growth factor (immunosympathectomy), two treatments which result in a massive loss of neurons in the ganglion. Daily injections of the polyamines putrescine, spermidine and spermine (10 mg/kg each), for 7 days after the operation to the axotomized group, and for 9 days starting with the first antiserum injection to the immunosympathectomized group, attenuated the nerve cell loss. The polyamine treatment also attenuated the reduction in the activity of the neurotransmitter-synthesizing enzyme tyrosine hydroxylase observed after both axotomy and immunosympathectomy in the ganglion. These results further indicate that polyamines are important for the survival of sympathetic neurons and, while their mechanism of action is unknown, an interaction with nerve growth factor regulation cannot be excluded. In the iris, the reduction observed in [3H]norepinephrine uptake after the two noxious treatments was unproportionately small when compared to the large drop in the number of parent neurons in the ganglion. This suggests that compensatory mechanisms exist which act to adjust the number of functional axon terminals per neuron so that the number of terminals innervating the target remains relatively constant.

Animals↗
PubMed1994

Ornithine decarboxylase activity and polyamine concentrations in fetal rat brain: response to chronic hypoxic-hypoxia and/or carbon monoxide-hypoxia.

Ornithine decarboxylase activity (ODC; E.C. 4.1.1.17), is significantly elevated in fetal and newborn rat brain in response to acute hypoxia. Because relatively little is known about ODC activities and polyamine metabolism in hypoxia and also because ODC and the polyamines are essential for normal growth and development, we examined the effect of chronic maternal hypoxic-hypoxia (16-10.5% O2), carbon monoxide-hypoxia (100-200 ppm CO) and their combination, on fetal weight, fetal brain ODC activity and polyamine concentrations. Time-dated pregnant Sprague-Dawley rats were chronically exposed to hypoxia from gestational day (E-15), to gestational day 21 (E-21), in individual chambers. Pair-fed controls were given an amount equivalent to that eaten by a hypoxic dam over the previous 24 h. We measured fetal weight, as well as brain ODC activity and polyamine concentrations on both E-19 and E-21. Pair-feeding had no effect on fetal weight, ODC activity or polyamine concentrations. On both E-19 and E-21, however, fetal weights were significantly reduced with higher levels of hypoxic-hypoxia (e.g., 10.5% O2). At 100 or 200 ppm, carbon monoxide alone appeared not to affect fetal weight; however, combined with even mild hypoxia (16% O2), fetal weights were reduced almost 20%, suggesting that together, CO- and hypoxic-hypoxia exert a synergistic effect of fetal weight decrements. (1) There was no consistent pattern of ODC activity changes which correlated to the fetal weight losses or levels of hypoxia. These results suggest that ODC activity may not be a good marker for chronic, as opposed to acute hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

On the translational control of ornithine decarboxylase expression by polyamines.

Ornithine decarboxylase (ODC, EC 4.1.1.17) expression is subject to negative feedback regulation by the polyamines. The results of previous studies favor either translational or post-translational regulation. To facilitate further analysis of the mechanism by which polyamines affect ODC expression we have used a cell line (L1210-DFMOr) that overproduces ODC. This cell line was isolated by selection for resistance to the antiproliferative effect of the ODC inhibitor alpha-difluoromethylornithine (DFMO). These cells respond similarly to polyamine depletion and repletion as do their wild-type counterparts. When L1210-DFMOr cells were grown in the presence of 20 mM DFMO (i.e., when their polyamine content was reduced to an extent that still permitted a normal growth rate) ODC represented 4-5% of the soluble protein synthesized. After transfer of the cells to a medium lacking DFMO (i.e., when their polyamine pools were repleted), the rate of incorporation of [35S]methionine into ODC was one order of magnitude lower. Since this difference in incorporation of radioactivity into ODC remained the same irrespective of the pulse-label time used (between 2 and 20 min) it is likely to represent a true difference in ODC synthesis rate. Consequently, the pulse-label experiments cannot be explained by rapid degradation of the enzyme during the labeling period. The difference in ODC synthesis rate was not accompanied by a corresponding difference in the steady-state level of ODC mRNA. Analyses of the distribution of ODC mRNA in polysome profiles did not demonstrate any major difference between cells grown in the absence or presence of DFMO, even though the ODC synthesis rate differed by as much as 10-fold. However, the distribution of the ODC mRNA in the polysome profiles indicated that the message was poorly translated. Thus, most of the ODC mRNA was present in fractions containing ribosomal subunits or monosomes. Inhibition of elongation by cycloheximide treatment resulted in a shift of the ODC mRNA from the region of the gradient containing ribosomal subunits to that containing mono- and polysomes, indicating that most of the ODC mRNA was accessible to translation. Taken together these data lend support to a translational control mechanism which involves both initiation and elongation.

Eflornithine↗
PubMed1985

The characterization and regulation of a polyamine-responsive, cyclic nucleotide-independent protein kinase activity in the mouse mammary gland.

The existence of two cyclic nucleotide-independent protein kinases in the cytosolic extract of mouse mammary gland has been determined via DEAE-cellulose and Sephacryl column chromatography. Both enzymes phosphorylated casein in the absence of the exogenous cyclic nucleotides, cAMP and cGMP. One protein kinase was found to have a molecular weight of approx. 30 000, while the other was found to have a molecular weight in the range 150 000-250 000. The activity of the larger species was enhanced by polyamines and inhibited by heparin. This enzyme utilized both ATP and GTP as phosphate donors; the apparent Km values were 10 and 16 microM, respectively. The lower molecular weight protein kinase was not affected by either polyamines or heparin and utilized only ATP (Km = 8 microM) as the phosphate donor. The polyamine-responsive protein kinase activity in the mammary gland varied as a function of the reproductive development of the mouse. The activity was relatively low in the virgin and primiparous stages, increased during pregnancy and peaked during lactation. Studies using mammary organ culture indicated that the combination of insulin (5 micrograms/ml), cortisol (1 micrograms/ml) and prolactin (5 micrograms/ml) maintained the polyamine-responsive protein kinase activity that was present in noncultured tissue. In the absence of prolactin, however, the kinase activity was significantly lower than that observed in the three-hormone system. When dibutyryl cyclic AMP (0.5 mM) was added to the medium along with the three hormones, a significant decrease in enzyme activity was found. Slab gel electrophoresis and autoradiography showed that the majority of the phosphorylated endogenous substrates in the cytosolic fraction were caseins. The results of this study suggest that the polyamine-responsive protein kinase may play an important role in the growth and development of the mammary gland.

Adenosine Triphosphate↗
PubMed1990

Interactions between growth factor secretion and polyamines in MCF-7 breast cancer cells.

Polyamines may be involved in hormone-dependent breast cancer cell proliferation. The antiestrogen 4-hydroxy-tamoxifen and the polyamine synthesis inhibitor alpha-difluoromethylornithine (DFMO) inhibited MCF-7 growth, and this effect was additive. Transforming growth factor beta (TGF-beta) levels were increased by both compounds; again the effect was additive. Exogenous putrescine antagonized DFMO but not the antiestrogen. However, exogenous TGF-beta did not inhibit cell growth. Secretion of insulin-like growth factor 1 (IGF-1) was not affected by DFMO-induced polyamine depletion but 4-hydroxytamoxifen increased IGF-1, which suggests an estradiol-like effect. Thus polyamines are involved in basal TGF-beta secretion but do not mediate antiestrogen-induced TGF-beta secretion. IGF-1 secretion by MCF-7 cells is not under polyamine control. The antiproliferative effects of 4-hydroxytamoxifen and DFMO cannot be accounted for by either suppression of IGF-1 secretion (a growth stimulatory factor) or stimulation of TGF-beta production (a growth inhibitory polypeptide).

Breast Neoplasms↗
PubMed1994

Inhibitory effects of cyclosporin A on rat insulinoma cell proliferation, polyamine content and insulin secretion.

The effects of the immunosuppressive drug cyclosporin A on the growth and secretion of clonal rat insulinoma cells (RINm5F) was investigated in vitro. Particular attention was paid to the influence of cyclosporin A on the metabolism of polyamines, since these compounds have been implicated in regulation of the growth and function of insulin-producing cells. It was found that culture of the cells for 2 days in the presence of 0.1 mg/l of cyclosporin A failed to affect RINm5F cell proliferation, polyamine content, cellular insulin content or secretion of insulin into the culture medium. When the concentration of cyclosporin A was raised to 1 mg/l, however, the growth rate and polyamine content of the cells were impeded in parallel with a decreased cellular insulin content and insulin secretion. Replenishment of the intracellular polyamine content by addition of exogenous putrescine failed to prevent the decreased growth rate and insulin content, indicating that cyclosporin A does not exert its inhibitory effect on the growth and insulin content of the RINm5F primarily by decreasing the polyamine content of these cells. Hence, cyclosporin A may be useful in decreasing the rapid growth of insulin-producing tumor cells, but also impairs insulin secretion.

Animals↗
PubMed1992

The polyamine diaminodecane (DA-10) produces a voltage-dependent flickery block of single NMDA receptor channels.

Receptor binding assays have shown that diaminodecane (DA-10) reduced binding of open channel blockers to the N-methyl-D-aspartate (NMDA) subtype of postsynaptic glutamate receptor through an interaction with the polyamine regulatory site. Because the action of DA-10 was opposite to that of the polyamine agonist spermine and was reversed by polyamine antagonists, DA-10 has been classified as an inverse agonist at the polyamine site. Using whole-cell voltage-clamp and single-channel recordings from cultured rat cortical neurons, we show that at negative holding potentials DA-10 (1-300 microM) reduced NMDA receptor whole cell current (IC50 = 34 microM) and produced a flickery block of NMDA single-channel currents. The flickery block of NMDA single channels was voltage-dependent and not reversed by the polyamine antagonist diethylenetriamine (DET). Potential mechanisms for the flickery block of NMDA single channel currents are discussed.

Animals↗
PubMed1994

Polyamines inhibit nitric oxide synthase in rat cerebellum.

The polyamines spermine, spermidine and putrescine share some basic structural features with L-arginine, the substrate of nitric oxide (NO) synthase. The effects of the polyamines on neuronal NO synthase activity were studied in cytosolic preparations of rat cerebellum and cultured cerebellar granule neurons. Spermine, spermidine and putrescine all inhibited the conversion of [3H]L-arginine to [3H]L-citrulline by NO synthase, with the following rank order of potency: spermine > spermidine > putrescine. These inhibitory effects of the polyamines on [3H]L-citrulline formation were also observed in intact cultured cerebellar granule neurons upon stimulation of N-methyl-D-aspartate (NMDA) receptors. Evidence was obtained, however, that endogenous polyamines are not involved in regulation of NMDA-stimulated NO synthase activity. Thus, the observed inhibitory effects of exogenous polyamines might not reflect a physiological role in modulating NO generation in neurons.

Amino Acid Oxidoreductases↗
PubMed1995

Brain polyamine levels are altered in Alzheimer's disease.

Despite considerable evidence implicating polyamines in CNS function, little is known about the status of the polyamine system in normal or abnormal human brain. We measured the levels of the polyamines spermidine, spermine and their precursor putrescine, in cortical and subcortical areas of 12 patients with Alzheimer's disease (AD). As compared with the controls, mean levels of spermidine were markedly and significantly increased (70%) whereas putrescine levels were decreased (28%) in temporal cortex of the AD patients. No other statistically significant changes were observed with the exception of a mean 35% reduction in spermine concentration in occipital cortex. In view of the modulatory effects of polyamines on calcium flux and glutamate receptor function, our data suggest that abnormal polyamine system activity may be involved in the neurodegenerative processes occurring in brain of patients with AD.

Aged↗
PubMed1979

Regulation of the immune response by polyamines.

Regulation of the immune system is accomplished, in part, by numerous soluble factors and small molecules. One such class of regulatory substances may be the polyamines which are present in a variety of tissues. Stimulation of the immune response often occurs by crosslinking of lymphocyte surface proteins, followed by the production of some transmembrane signal. The activation pathway may be interrupted if certain necessary steps are blocked. It is proposed that polyamines exert regulatory influences by modulating crosslink formation; a step catalyzed by the enzyme transglutaminase. A model is outlined which describes the events initiating lymphocyte activation and the role of polyamines in this process. Certain drugs which might mimic the actions of polyamines are also discussed. During evolution of the control of growth processes in cells, relatively simple molecules (the polyamines) may have assumed a pivotal role in initiating and terminating the proliferative response. This idea has been applied to regulation of the immune system.

Animals↗
PubMed1995

Polyamine involvement in the cell cycle, apoptosis, and autoimmunity.

The polyamines: putrescine, spermidine and spermine, are ubiquitous polycations which have numerous, unique interactions in eukaryotic cells. Polyamines are essential for cell growth, with the bulk of polyamine expression co-ordinated with the cell cycle. The length, charge, and charge distribution of polyamines permit them to interact with large anionic molecules such as DNA, RNA, and phospholipids. Here, a mechanism is proposed whereby cell cycle expression of polyamines at the start of S phase leads to disruption of transcription and splicing, giving priority to DNA and histone synthesis. Inappropriate initiation of this process in non-viable cells leads to apoptosis and may be an underlying cause of autoimmunity.

Animals↗
PubMed1995

Slowing proliferation in head and neck tumors: in vitro growth inhibitory effects of the polyamine analog BE-4-4-4-4 in human squamous cell carcinomas.

PURPOSE: These preclinical studies were carried out to examine the potential of the antiproliferative polyamine analog 1,19-bis-(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) to serve as a therapy adjuvant to radiation for patients with rapidly dividing tumors of the head and neck (H&N). METHODS AND MATERIALS: Cytostatic and cytotoxic effects of this polyamine analog were investigated in three squamous cell carcinoma (SCC) cell lines derived from human H&N tumors. RESULTS: Growth inhibition was achieved in all cell lines within 3-4 days of continuous 10 microM drug exposure, and inhibition of cell cycle proliferation kinetics was confirmed via flow cytometry. Cytotoxicity was pronounced (3-4 log cell kill) in the SCC-38 and SCC-4Y cell lines with continuous 10 microM analog exposure over 5 days, and was minimal in the SCC-13Y cell line. No demonstrable effect of BE-4-4-4-4 on single dose radiation survival was identified in any SCC cell line. Ornithine decarboxylase (ODC) activity was rapidly inhibited (1-2 h) following 10 microM BE-4-4-4-4 exposure in all SCC cell lines (approximately 90%), whereas identical exposure to 10 microM difluoromethylornithine (DFMO) induced animal ODC inhibition (approximately 10%). Dose-dependent depletion of endogenous polyamines (putrescine, spermidine, spermine) was achieved in all SCC cell lines following 1 microM and 10 microM BE-4-4-4-4 exposures. Difluoromethylornithine was significantly less potent than BE-4-4-4-4 in its capacity to deplete endogenous polyamines, with no measureable depletion of spermine pools even with 5 mM x 48 h DFMO exposures. CONCLUSIONS: These data evaluate cytostatic and cytotoxic properties of the polyamine analog BE-4-4-4-4 in human SCCs, and suggest a role for investigation of such agents as an adjuvant to radiation in the therapeutic approach to rapidly dividing human tumors such as those that occur in the H&N.

Carcinoma, Squamous Cell↗
PubMed1986

Fetal calf serum-mediated toxicity of human polyamines to lymphocytes.

The toxicity of polyamines in the presence of fetal calf serum (FCS) to resting and stimulated human lymphocytes was investigated. Polyamines were cytotoxic to resting lymphocytes in the presence of FCS in a dose-dependent manner. The order of toxicity was: spermine greater than spermidine greater than putrescine. Blastogenic responses of human lymphocytes were also suppressed by spermine and spermidine but not putrescine. The lymphocytes which respond to PWM were most sensitive to polyamine toxicity. Superoxide dismutase, catalase and mannitol were ineffective in preventing the toxicity of polyamines. The sensitivity to polyamine toxicity of lymphocytes varied with age of the lymphocyte donors.

Aging↗