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PubMed1989

Modulation of growth gene expression by selective alteration of polyamines in human colon carcinoma cells.

The biosynthesis of the polyamines, putrescine, spermidine and spermine, is temporally linked with expression of many growth related genes. Our previous studies have shown that generalized polyamine depletion of the human colon cancer cell line COLO 320 by 2-difluoromethylornithine is associated with decreased transcription of the c-myc, c-fos, and ornithine decarboxylase (ODC) genes. In the current study, the role of individual polyamines was further defined by the use of a specific inhibitor of spermidine synthase, S-adenosyl-1,8, diamino-3-thio-octane (AdoDATO), and a spermine analogue, N1,N12 bis(ethyl)spermine. Our data demonstrate that depletion of spermidine results in a 60-90% decrease in c-myc mRNA steady state levels. In contrast, c-fos mRNA levels are decreased only when both spermidine and spermine are diminished. Furthermore, ODC mRNA levels are increased when all polyamines are decreased by DFMO, but are unaffected by a selective reduction in intracellular spermidine levels by AdoDATO. These studies suggest that individual polyamines may have a selective role in the expression of specific growth related genes.

Adenosine↗
PubMed1991

Effects of polyamine analogs on the extent and fidelity of in vitro polypeptide synthesis.

A series of polyamine analogs has been examined for their ability to support protein synthesis in an in vitro rabbit reticulocyte translation system. Diamines were found to stimulate protein synthesis to the greatest extent (8-12 fold). Triamines, tetraamines and pentaamines only stimulated 2-4 fold under these conditions although much lower concentrations were required. At elevated temperatures (45 degrees C), diamines were somewhat more active than at lower temperature but activity of longer chain polyamines was elevated very significantly. Polyamines with terminal benzyl or smaller alkyl groups had diminished activity. It is concluded that both charge and charge distribution determine the ability of polyamines to stimulate translation. Fidelity studies identified two classes of polyamines: those which are able to lower the optimal Mg2+ concentration required for amino acid misincorporation while not affecting extent of misincorporation relative to Mg2+ alone, and those which are sparing for Mg2+ and also stimulate extent of misincorporation.

Animals↗
PubMed1990

Stimulation and inhibition of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced strand breaks and interstrand cross-linking in Col E1 plasmid deoxyribonucleic acid by polyamines and inorganic cations.

The influence of various polyamines and metallic cations on 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-induced DNA single-strand breaks and DNA interstrand cross-linking was in Col E1 plasmid using electrophoretic techniques. Spermidine and spermine (0.4 to 1.5 mM concentration range) markedly stimulated BCNU-induced DNA nicking, whereas putrescine had no effect on the nicking process. In contrast to the polyamines, BCNU-induced DNA nicking was decreased by the three inorganic cations, Na+ (100 and 200 mM), Mg2+ (0.5 and 1.5 mM), and Co3+ (NH3)6 (0.2 and 0.4 mM), with the trivalent hexamminecobalt ions being most inhibitory. When the monofunctional N-methyl-N-nitrosourea (MNU) was used (instead of the bifunctionally active BCNU) to alkylate Col E1 DNA, nicking of the DNA was inhibited by spermidine. Furthermore, the ability of chloroethylated Col E1 DNA to form interstrand cross-links after treatment with BCU was inhibited by 0.5 mM spermidine and 0.5 mM spermine, both concentrations within the intracellular range. Putrescine at 3-6 mM only marginally stimulated DNA cross-linking. In comparison, the inorganic cations all enhanced Col E1 DNA cross-linking by BCNU, with the rank order of cross-link stimulation being Mg2+, Na+, and Co3+ (NH3)6. These results provide evidence that polyamines can interact with DNA to modulate chloroethylnitrosourea-induced DNA damage and that the interaction is not only a function of the charge on the polyamine molecule but also of the chemical structure of the polyamine.

Carmustine↗
PubMed1994

Lithium exerts a time-dependent and tissue-selective attenuation of the dexamethasone-induced polyamine response in rat brain and liver.

It has previously been shown that chronic, but not acute, lithium treatment indirectly prevents the dexamethasone-induced increase in brain polyamine-metabolizing enzymes. In the present study we determined the effects of lithium treatment on changes in cellular polyamines, 6 h after dexamethasone challenge (3 mg/kg intraperitoneally). The findings demonstrate that chronic lithium (daily intraperitoneal 2.5 mmol/kg injections for 2 weeks) treatment completely prevents the accumulation of putrescine, in parallel to its prevention of the dexamethasone-induced increase in ornithine decarboxylase activity. A partial attenuation of this polyamine response was also observed in the liver. Only minor and inconsistent changes were observed in the concentrations of the polyamines, spermidine and spermine. Acute lithium treatment (a single injection at times ranging from 1 to 24 h prior to dexamethasone challenge) did not attenuate the dexamethasone-induced increases in brain putrescine concentration nor in ornithine decarboxylase activity. It is suggested that prevention of the stress-induced polyamine response in the brain may be an important mechanism through which prophylactic lithium may exert its beneficial effect in manic-depressive illness.

Animals↗
PubMed1995

Increased polyamine levels and changes in the sensitivity to convulsions during chronic treatment with cocaine in mice.

Polyamines have been demonstrated to modulate seizure activity in animals. Repeated administration of a subthreshold dose of cocaine resulted in the development of sensitization to cocaine-induced seizures during an initial 3 or 4 days, followed by the development of tolerance to seizures on days 5 and 6. In the present study, polyamines, such as putrescine, spermidine and spermine, were measured in regions of the brain obtained from mice that showed differential sensitivity in seizure activity during repeated cocaine injections. Animals were sacrificed for polyamine measurements 24 h after the second and the fifth injections of either cocaine or saline (on day 3 and day 6, respectively), and 3 days after the last injection. On day 3, there were significant increases in putrescine in the striatum, hippocampus and cerebellum, and in spermine in the cerebellum of cocaine-treated mice, as compared to saline-treated mice. On day 6, treatment with cocaine significantly increased putrescine in all regions, and spermidine in striatum and hippocampus, as compared to saline treatment. Cocaine treatment had no effect on any polyamine levels measured 3 days after the last injection, except for spermidine in the cortex. Because putrescine has been shown to be an antagonist of the polyamine-binding site on the N-methyl-D-aspartate receptor and to retard the development of amygdala-kindling, the present results suggest that the increases in putrescine content may be associated with the development of tolerance to convulsant effects observed during the later period of repeated administration of cocaine.

Animals↗
PubMed1986

Ornithine decarboxylase induction and polyamine biosynthesis are required for the growth of interleukin-2- and interleukin-3-dependent cell lines.

The objective of this study was to evaluate induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, and subsequent polyamine accumulation in interleukin-2 (IL-2)- and interleukin-3 (IL-3)-dependent growth. The CTLL-20 and FDC-P1 cell lines, which have been shown to be absolutely dependent on IL-2 and IL-3, respectively, were used in these studies. The CTLL-20 and FDC-P1 cells each had different temporal patterns of ODC induction following lymphokine stimulation. ODC levels increased rapidly in the FDC-P1 cells, peaking 4 hr after stimulation with IL-3. In contrast, peak ODC activity in the CTLL-20 cells occurred 18 hr following stimulation with IL-2 and reached eightfold higher levels than those observed in the FDC-P1 cells. Treatment with D,L-alpha-difluoromethylornithine X HCl X H2O (DFMO), a specific irreversible inhibitor of ODC activity, completely abrogated lymphokine-dependent ODC induction in both the CTLL-20 and FDC-P1 cell lines. Similarly, intracellular levels of the polyamines putrescine and spermidine were reduced in both cell lines following DFMO treatment. DFMO treatment reduced both IL-2- and IL-3-dependent proliferation in a dose-dependent manner. However, this inhibition could be reversed by the addition of exogenous putrescine. DFMO treatment had no effect on cell viability. Polyamine-depleted CTLL-20 and FDC-P1 cells showed decreased absorption of IL-2 and IL-3 activity, respectively. However, the addition of exogenous putrescine restored the ability of the cells to absorb the appropriate lymphokine. These data are the first to demonstrate that ODC induction and polyamine biosynthesis are required in lymphokine dependent growth.

Cell Division↗
PubMed1979

Isolation and characterization of a polyamine-peptide conjugate from human amniotic fluid.

Significant amounts of the diamine putrescine and the polyamines spermidine and spermine could be detected in human third-trimester amniotic fluid only after acid hydrolysis. This observation was interpreted to mean that these amines existed only in conjugated form in this biological fluid. Upon fractionation by ultrafiltration 90--10% of the putrescine was associated with the 1000--10 000 dalton fraction. Spermine was identified in this fraction and in a low-molecular weight fraction presumably representing acetylated derivatives. Spermidine was entirely associated with the 10 000--30 000 dalton fraction. The putrescine conjugate was purified to homogeneity by column chromatography on Biogels P10 and P6 followed by ion-exchange chromatography on DEAE-Sephadex A-25. Molecular weight by gel exclusion using peptide standards was estimated to be approx. 4600. The UV absorption spectrum of the putrescine conjugate conformed to that expected for a polypeptide. This putrescine conjugate contained 39 identified amino acids with a combined molecular weight of 4713. Putrescine was detectable by high pressure liquid chromatography only after acid hydrolysis of the conjugate. No other polyamines were detected in these hydrolyzates, nor were any polyamines demonstable in hydrolyzates of control peptides nor in pooled column washes. The identity of the putrescine determined by high pressure liquid chromatography was confirmed by a two-dimensional thin-layer chromatography method. These results establish the in vivo production of a putrescine--polypeptide conjugate in man. Such molecular species may constitute yet another metabolic pathway for polyamines or may reflect another mode of post-translational modification of polypeptide structure and function. The qualitative and quantitative analysis of polyamine conjugate in human aminotic fluid may prove to be useful in the detection of abnormalities in fetal development.

Amino Acids↗
PubMed1990

Urinary polyamine and metabolite excretion by children with Zellweger's syndrome.

In order to investigate whether, due to a lack of peroxisomes, polyamine degradation is altered in patients with the cerebro-hepato-renal syndrome of Zellweger, we determined total, free and acetylated polyamines and some of their catabolites in urines of six patients and age-matched healthy children. The normal polyamine excretion patterns of the patients, compared to the control group, suggest that either the intracellular localisation of the polyamine degrading enzyme, polyamine oxidase, is not exclusively limited to peroxisomes or that the enzyme is located in the peroxisomal matrix.

Amino Acids, Diamino↗
PubMed1987

Modulation of arterial smooth muscle cells from contractile to synthetic phenotype requires induction of ornithine decarboxylase activity and polyamine synthesis.

The role of polyamines in modulating cultivated arterial smooth muscle cells from contractile to synthetic phenotype was studied by biochemical and electron microscopic methods. Ornithine decarboxylase (ODC), the first and overall rate-limiting enzyme in polyamine biosynthesis, showed no detectable activity in freshly isolated contractile cells, rose to a peak of activity after 2 days of culture, simultaneously with the most rapid phase of phenotypic modulation, and thereafter returned to a lower level of activity. The increase in ODC activity was accompanied by a gradual rise in the cellular concentrations of the polyamines putrescine, spermidine and spermine. The polyamine synthesis inhibitors alpha-difluoromethylornithine and methylglyoxal-bis(guanylhydrazone) prevented transition into synthetic phenotype as well as initiation of cell growth. The results indicate that polyamines play an important role in the control of smooth muscle phenotype and growth.

Animals↗
PubMed1983

Polyamines in normal and cataractous human lenses: evidence for post-translational modification.

The polyamine composition of normal and cataractous human lenses has been studied. Polyamines (putrescine, spermidine and spermine) have been shown to occur in the unbound form in the acid-soluble fraction and in the bound form in the acid-insoluble fraction of the lens. It has also been shown that only putrescine occurs in both conjugated and non-conjugated states in the lens, while putrescine as well as spermidine occur in both forms in the aqueous fluid. Estimation of the polyamine content in cataractous lenses indicates elevated levels of both bound and unbound polyamines in these lenses in comparison to the normal lenses. Evidence is presented which indicates an increase in the level of polyamines covalently bound to protein, in a gamma-glutamyl linkage, in the cataractous lens.

Aged↗
PubMed1983

Leishmania tropica major: effect of paromomycin and pentamidine on polyamine levels in the skin of normal and infected mice.

The polyamine content of the skin of BALB/c and C3H mice was determined at intervals, after injecting Leishmania tropica major. In BALB/c mice, putrescine and spermidine levels increased three- to seven-fold; in C3H mice, spontaneous recovery occurred after 3 weeks, accompanied by a reduction in putrescine and spermidine levels. Ornithine decarboxylase activity was negligible in normal, uninfected skin of both BALB/c and C3H mice, but increased steadily during infection. Treatment with drugs that inhibit the growth of leishmanial amastigotes in the skin of mice also reduced polyamine levels and ornithine decarboxylase activity of previously infected skin. There was a close correlation between the therapeutic activity of the drugs and their effect on polyamine content and synthesis. The aminoglycoside paromomycin, which was chemotherapeutically more effective than pentamidine, also had a greater effect on polyamine levels. S-adenosyl-L-Methionine decarboxylase activity in the skin of BALB/c and C3H mice was only slightly affected by the parasites. Polyamine levels and ornithine decarboxylase activity could possibly serve as means for measuring the growth of leishmanial parasites in skin and other tissues and as a measure of the efficacy of anti-leishmanial chemotherapeutics.

Adenosylmethionine Decarboxylase↗
PubMed1995

Polyamine induced Z-conformation of native calf thymus DNA.

Conformational isomerization of native calf thymus DNA under the influence of spermine, spermidine and putrescine was monitored by UV absorption and immunospecific anti-Z-DNA antibodies. Immunological data indicated increased binding of anti-Z-DNA antibodies to polyamine-perturbed conformations of native DNA and double stranded poly(dG-dC). In the absence of polyamines, anti-Z-DNA antibodies did not bind to either polymers. Analysis of UV absorption studies indicates a left handed conformation of nDNA in the presence of polyamines. Moreover, we observed total aggregation of DNA in the presence of spermine on prolongued incubation. These perturbations in conformation were dependent on polyamine concentration. The results clearly suggest that certain regions of nDNA are sensitive to elevated levels of polyamines and are capable of undergoing B-->Z transition.

Animals↗
PubMed1991

Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats.

This investigation shows whether polyamines and ornithine decarboxylase have a role in duodenal mucosal repair following stress-induced microscopic damage. Rats were fasted for 22 hours, placed in restraint cages, and immersed in water to the xiphoid process for 6 hours. Animals were killed either immediately after the period of stress or at 2-hour intervals up to 24 hours thereafter. Duodenal mucosa was examined histologically, and ornithine decarboxylase and polyamine levels were measured. Ornithine decarboxylase activity was increased significantly up to 6 hours following stress, peaking at 4 hours at a level 10 times the prestress control. By 8 hours, enzyme activity had returned to near normal. Increases in mucosal putrescine, spermidine, and spermine content paralleled the changes in ornithine decarboxylase activity and peaked 4 hours after stress. Stress resulted in microscopic damage evidenced by a nearly complete absence of villi. Significant macroscopic lesions were not present following stress. Mucosal repair was evident 12 hours after stress and almost complete by 24 hours, although the restituted villi were short and blunted. The decreases in mucosal DNA, RNA, and protein content caused by stress were restored and reached near-normal levels 12 hours after the period of stress. In animals given the specific inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine, increases in duodenal mucosal ornithine decarboxylase activity and polyamine levels were inhibited and mucosal repair was almost completely prevented following stress. alpha-Difluoromethylornithine also prevented the recovery of DNA, RNA, and protein content of the duodenal mucosa. These results indicate that duodenal mucosal damage following stress is repaired rapidly; the repair process is accompanied by significant increases in ornithine decarboxylase activity and polyamine levels; and the increases in ornithine decarboxylase and polyamines are absolutely required for the normal repair of the mucosa.

Animals↗
PubMed1987

Quantitative structure activity relationship studies on the activation of yeast AMP deaminase by polyamines.

Quantitative structure activity relationship studies on the activation of AMP deaminase by polyamines were carried out. Polyamine enhanced the maximal velocity of AMP deaminase without changing the affinity for the substrate AMP. Activation by polyamines of AMP deaminase can be accounted for by the simple Michaelis-Menten mechanism in the presence of ATP. A close correlation between the structure and activation constants for polyamines suggests that the binding of polyamine to AMP deaminase involves primarily polar interactions.

AMP Deaminase↗
PubMed1989

Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism.

1. Inactivation of L-ornithine:2-oxoacid aminotransferase (OAT) by 5-fluoromethylornithine (5FMOrn), a specific inactivator of OAT, causes a great elevation of tissue ornithine (Orn) concentrations. 2. Inhibition of L-ornithine decarboxylase (ODC) by 2-difluoromethylornithine (DFMO) had no effect on Orn concentrations. 3. The combined administration of 5FMOrn and DFMO produced a 2- to 3-fold greater enhancement of tissue Orn concentrations than treatment with 5FMOrn alone. 4. The increase of tissue Orn concentrations had a long-lasting enhancing effect on polyamine metabolism. 5. In the brain this could be demonstrated by the elevation of putrescine and spermidine concentrations and the increase of spermidine turnover rate. 6. In visceral organs polyamine concentrations were not elevated because polyamines can be eliminated by transport. 7. In line with this notion is the fact that urinary polyamine excretion was increased for several days, even after a single dose of 5FMOrn. 8. Inhibitors of 4-aminobutyric acid:2-oxoglutarate aminotransferase which are also inactivators of OAT had the same effect on polyamine excretion as 5FMOrn.

Animals↗
PubMed1995

Involvement of polyamines in the contragestational effect of hyperthermia.

Although hyperthermia produces teratogenic effects in a great variety of animal species, the molecular mechanisms by which hyperthermia exerts its action remain unknown. We have studied the implications of polyamines in contragestational hyperthermia in rats. Our results show that the contragestational action of hyperthermia when applied in consecutive periods during days 8, 9 and 10 of rat pregnancy could be completely prevented by the previous administration of polyamines (putrescine and spermidine, 0.6 mmoles/kg and 0.03 mmoles/kg respectively) in combination with the diamine oxidase inhibitor aminoguanidine or by this inhibitor alone (0.12 mmoles/kg). The administration of polyamines alone partially prevented the fetotoxic effect of hyperthermia but produced a marked mortality (50%) in the pregnant rats. These findings support a major and complex role of polyamines in the mechanisms of hyperthermia-mediated teratogenesis, and suggest that the oxidative catabolism of polyamines could be in part responsible of the deleterious effect produced by hyperthermia in rat pregnancy.

Amine Oxidase (Copper-Containing)↗
PubMed1989

Polyamine levels as biomarkers of injury response in polytrauma victims.

Enhanced protein mobilization and synthesis are common responses to severe trauma. The hypothesis that extracellular polyamine levels could be valid biomarkers for these responses has been investigated. The three polyamines, spermidine, spermine and their precursor putrescine are directly involved in cell growth/death kinetics through regulation of protein metabolism. The lack of tissue uptake of extracellular polyamines and their rapid conjugation and excretion make them excellent biomarkers of variations in cellular kinetics. The polyamine levels in plasma and urine of severely traumatized patients were measured during the early "flow" phase of injury and compared with unstressed normals. Significantly elevated urinary levels of free and total putrescine and spermidine indicate the increase in the protein synthesis and breakdown rates, respectively, in polytrauma patients. Urinary spermidine level correlates well with other known parameters of protein catabolism, such as isotopically measured whole body protein breakdown rate in the basal state and 3-methylhistidine excretion and nitrogen loss in the basal condition and during nutritional therapy. Whole-body protein synthesis rate positively correlates with putrescine levels in urine. Based on these observations, urinary levels of the polyamines spermidine and putrescine may be applied as valid biomarkers of protein breakdown and synthesis rates, respectively, both for the existing pathology of severe trauma and for the response to nutritional therapy.

Adult↗
PubMed1993

Polyamine modulation of excitatory amino acid responses in the rat cortical wedge.

Rat neocortex slices in Mg2+ free buffer show spontaneous discharges which have a constant frequency and are dependent on N-methyl-D-aspartate (NMDA) receptor activation. Spermine increased the frequency of discharges at concentrations below 1 mM, had biphasic effects at 1 mM, and only decreased the frequency of discharges at 3 mM. In contrast, the amplitude of these discharges was only reduced by spermine in a concentration dependent manner (300 microM to 3 mM). Spermidine produced similar effects, but was a less potent inhibitor of discharge frequency and amplitude than spermine. Diethylenetriamine (DET) 300 microM did not significantly inhibit polyamine-induced increases in the discharge frequency. Polyamines inhibited direct depolarizations induced by the glutamate agonists NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in a concentration and time dependent manner. The data are consistent with two sites of action for polyamines, one enhancing the frequency of NMDA-mediated spontaneous epileptiform discharges and the other inhibiting direct glutamate responses in rat cortex. The slow onset (time to maximal enhancement or inhibition by polyamines greater than 30 min) and lack of reversibility with polyamine removal suggest that these sites are intracellular and/or presynaptic.

Amino Acids↗