Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biogenic Polyamines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed1995

Polyamines and NMDA receptors modulate pericapillary astrocyte swelling following cerebral cryo-injury in the rat.

Four hours following cryo-injury rat cerebral pericapillary astrocytes from the perilesional area were markedly swollen occupying 17% of the pericapillary space as compared to 11% in sham operated controls. Ornithine decarboxylase activity and polyamine levels were increased over sham controls. The astrocytic swelling, the percentage of the pericapillary space occupied by astrocytic processes, and polyamine levels were reduced to near control levels by the following: (1) alpha-difluoromethylornithine; (2) Ifenprodil; and (3) MK-801. alpha-Difluoromethylornithine is a specific inhibitor of ornithine decarboxylase, Ifenprodil is an inhibitor of the polyamine binding site on the n-methyl-d-aspartate receptor, and MK-801 is an antagonist to n-methyl-d-aspartate binding to the n-methyl-d-aspartate receptor. Addition of putrescine, the product of ornithine decarboxylase activity, reversed the effect of alpha-difluoromethylornithine and restored the pericapillary swelling. Putrescine did not affect the MK-801-induced reduction in pericapillary astrocytic swelling. Therefore, polyamines and the n-methyl-d-aspartate receptor modulate excitotoxic responses to cryo-injury in pericapillary cerebral astrocytes.

Animals↗
PubMed1988

Role of polyamines in the growth of hormone-responsive experimental breast cancer in vivo.

We have provided evidence for a critical role of polyamines in the growth of the hormone-responsive N-nitrosomethyl-urea (NMU)-induced rat mammary tumor in vitro. The present experiments were designed to test whether polyamines are involved in the growth of this experimental tumor in vivo. To test this hypothesis, groups of rats bearing NMU-induced mammary cancers were randomly allocated to receive no treatment or escalating doses of the polyamine biosynthesis inhibitor alpha-difluoromethyl-ornithine (DFMO) (0.5%, 1%, 2%, 3% in drinking water). DFMO inhibited tumor growth in a dose-dependent fashion and consistently reduced tumor putrescine level. To evaluate the time dependency of this effect, additional groups of rats received either no treatment or 2% DFMO for 3, 7, 14, and 21 days. At all times DFMO suppressed tumor putrescine level as well as spermidine to spermine ratio. Finally, exogenous administration of putrescine (200 mg/kg/i.p./day x 21 days) given concomitantly with DFMO restored tumor growth, partially repleted tumor putrescine level, and raised the spermidine to spermine ratio to control levels. Putrescine, given alone, had no significant effect on either tumor polyamine levels or tumor growth. Except for modest weight loss, no major toxicity was encountered. These results indicate that polyamines play an important role in the growth of the NMU rat mammary tumor in vivo. The interaction between polyamines and hormones in supporting NMU mammary tumor growth in vivo remains to be elucidated.

Animals↗
PubMedDate not supplied

Inhibition of polyamine synthesis suppresses human lymphocyte proliferation without decreasing cytokine production or interleukin 2 receptor expression.

Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase (ODC), a crucial enzyme in polyamine synthesis, and impairs mitogen-induced lymphocyte proliferation. To examine the mechanism of action of DFMO, we studied the effect of this ODC inhibitor on lymphokine production and interleukin 2 (IL 2) receptor expression. DFMO decreased thymidine uptake of peripheral blood mononuclear cells stimulated by the mitogens phytohemagglutinin, concanavalin A, phorbol myristate acetate and ionomycin 60-70% compared with untreated cells, and the inhibition could be completely reversed by 10 mM spermidine. DFMO had no effect on IL 1 production by monocytes exposed to silica particles. Concentrations of IL 2 increased 7-fold in DFMO-treated, PHA-stimulated PBMC cultures, compared with untreated cells; whereas IL 2 receptor expression as measured by the anti-Tac monoclonal antibody was not affected by the inhibition of ODC. Mixing experiments using cells cultured with or without DFMO indicated that the inhibition by DFMO was not mediated by suppressor cells. Our results strongly support the concept that polyamines are required for a relatively late event in lymphocyte activation occurring after the interaction of IL 2 and its receptor.

Biogenic Polyamines↗
PubMed1989

Increased formation of N1-acetylspermidine in human breast cancer.

Mammary cancers were shown to contain large amounts of N1-acetylated derivatives of spermidine and spermine, whereas only small amounts of N1-acetylspermidine and no N1-acetylspermine were found in normal breast tissue. The elevated levels of monoacetylated polyamines were related to an increased activity of spermidine/spermine N1-acetyltransferase in the tumors. Acetylated polyamines can be excreted in the urine and the present study raises the question whether these conjugates may be of any value as biological markers for neoplastic growth.

Acetyltransferases↗
PubMed2005

Polyamines: metabolism and implications in human diseases.

Classically, polyamines is a family of molecules (i.e. putrescine, spermine, spermidine) derived from ornithine according to a decarboxylation/condensative process. More recently, it has been demonstrated that arginine can be metabolised according to the same pathway leading to agmatine formation. Polyamines are essential for the growth, the maintenance and the function of normal cells. The complexity of their metabolism and the fact that polyamines homeostasis is tightly regulated support the idea that polyamines are essential to cell survival. Multiple abnormalities in the control of polyamines metabolism might be implicated in several pathological processes. This paper summarises the knowledge about polyamines metabolism and point out the importance of these molecules as a target for the development of therapeutic tools and nutritional strategy.

Acetylation↗
PubMed2001

Human DNA topoisomerase I inhibitory activities of synthetic polyamines: relation to DNA aggregation.

DNA aggregation by polyamines has acquired importance as a prerequisite for the cellular uptake of DNA for gene therapy. Intracellular polyamines are constitutive components of mammalian cells and their availability is critical for cell proliferation. Interference of polyamine biosynthesis by synthetic polyamines leads to cytotoxicity. Optimization of the polyamine structural parameters is necessary to control their DNA aggregation, cytotoxic or enzyme inhibitory activities. We designed two series of tetra- and hexamines and compared their human DNA topoisomerase I (top1) inhibitory effects with the DNA aggregation properties. We show that hexamines are more efficient inhibitors of DNA relaxation by top1 than tetramines and that they suppress the top1-mediated DNA cleavage while tetramines do not. The DNA aggregation abilities within two series of polyamines correlate with the length of their central methylene chain. By contrast, the top1 inhibition within two series does not show the same correlation but demonstrates a threshold inhibitory effect on going from the (CH(2))(12) to the (CH(2))(14) central chain. We show further that the structures of DNA aggregates formed by polyamines with the (CH(2))(10-12) or with the (CH(2))(14-16) chains are very different. The first are a fluid cholesteric-type phases, whereas the second are well-structured aggregates similar to columnar liquid crystals with high packing density of DNA duplexes. The structures of polyamines-induced DNA aggregates are proposed to be crucial for top1 catalysis. The structure-function correlation described here may serve as a guide for rational design of polyamines with desired DNA-aggregation or anti-top1 activities.

Base Sequence↗
PubMed1994

Polyamine-induced Z-DNA conformation in plasmids containing (dA-dC)n.(dG-dT)n inserts and increased binding of lupus autoantibodies to the Z-DNA form of plasmids.

Blocks of potential Z-DNA-forming (dA-dC)n.(dG-dT)n sequences are ubiquitous in eukaryotic genomes. We examined whether naturally occurring polyamines, putrescine, spermidine and spermine, could provoke the Z-DNA conformation in plasmids pDHf2 and pDHf14 with 23 and 60 bp inserts respectively of (dA-dC)n.(dG-dT)n sequences using an e.l.i.s.a. Spermidine and spermine could provoke Z-DNA conformation in these plasmids, but putrescine was ineffective. For pDHf2 and pDHf14, the concentration of spermidine at the midpoint of B-DNA to Z-DNA transition was 25 microM, whereas that of spermine was 16 microM. Polyamine structural specificity was evident in the ability of spermidine homologues to induce Z-DNA. Inorganic cations, Co(NH3)6(3+) and Ru(NH3)6(3+), were ineffective. Our experiments also showed increased binding of anti-DNA autoantibodies from lupus patients as well as autoimmune MRL-lpr/lpr mice to pDHf2 and pDHf14 in the presence of polyamines. These data demonstrate that small blocks of (dA-dC)n.(dG-dT)n sequences could assume the Z-DNA conformation in the presence of natural polyamines. Increased concentrations of polyamines in the sera of lupus patients might facilitate immune complex-formation involving circulating DNA and anti-Z-DNA antibodies.

Animals↗
PubMed2003

Transgenic mouse models for studies of the role of polyamines in normal, hypertrophic and neoplastic growth.

Transgenic mice expressing proteins altering polyamine levels in a tissue-specific manner have considerable promise for evaluation of the roles of polyamines in normal, hypertrophic and neoplastic growth. This short review summarizes the available transgenic models. Mice with large increases in ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase or antizyme, a protein regulating polyamine synthesis by reducing polyamine transport and ODC in the heart, have been produced using constructs in which the protein is expressed from the alpha -myosin heavy-chain promoter. These mice are useful in studies of the role of polyamines in hypertrophic growth. Expression from keratin promoters has been used to target increased synthesis of ODC, spermidine/spermine-N(1)-acetyltransferase (SSAT) and antizyme in the skin. Such expression of ODC leads to an increased sensitivity to chemical and UV carcinogenesis. Expression of antizyme inhibits carcinogenesis in skin and forestomach. Expression of SSAT increases the incidence of skin papillomas and their progression to carcinomas in response to a two-stage carcinogenesis protocol. These results establish the importance of polyamines in carcinogenesis and neoplastic growth and these transgenic mice will be valuable experimental tools to evaluate the importance of polyamines in mediating responses to oncogenes and studies of cancer chemoprevention.

Acetyltransferases↗
PubMed2000

Altered spermidine/spermine N1-acetyltransferase activity as a mechanism of cellular resistance to bis(ethyl)polyamine analogues.

To develop a model system to investigate mechanisms of antiproliferative action of bis(ethyl)polyamine analogues, intermittent analogue treatments followed by recovery periods in drug-free medium were used to select an N(1), N(12)-bis(ethyl)spermine-resistant derivative of the Chinese hamster ovary cell line C55.7. The resulting C55.7Res line was at least 10-fold resistant to N(1),N(12)-bis(ethyl)spermine and N(1), N(11)-bis(ethyl)norspermine. The stability of the resistance in the absence of selection pressure was >/=9 months, indicating that a heritable genotypic change was responsible for the resistance phenotype. Polyamine transport alterations and multi-drug resistance were eliminated as causes of the resistance. Spermidine/spermine N(1)-acetyltransferase (SSAT) activity and regulation were altered in C55.7Res cells as basal activity was decreased, and no activity induction resulted from exposure to analogue concentrations, which caused 300-fold enzyme induction in parental cells. SSAT mRNA levels in the absence and presence of analogue were unchanged, but no SSAT protein was detected in C55.7Res cells. A point mutation, which results in the change leucine156 (a fully conserved residue) to phenylalanine, was identified in the C55.7Res SSAT cDNA. Expression of wtSSAT activity in C55.7Res cells restored sensitivity to bis(ethyl)polyamines. These results provided definitive evidence that SSAT activity is a critical target of the cytotoxic action of these analogues.

Acetyltransferases↗
PubMed1999

Inhibition of polyamine synthesis arrests trichomonad growth and induces destruction of hydrogenosomes.

Trichomonad parasites such as Tritrichomonas foetus produce large amounts of putrescine (1,4-diaminobutane), which is transported out of the cell via an antiport mechanism which results in the uptake of a molecule of spermine. The importance of putrescine to the survival of the parasite and its role in the biology of T. foetus was investigated by use of the putrescine analogue 1, 4-diamino-2-butanone (DAB). Growth of T. foetus in vitro was significantly inhibited by 20 mM DAB, which was reversed by the addition of exogenous 40 mM putrescine. High-performance liquid chromatography analysis of 20 mM DAB-treated T. foetus revealed that putrescine, spermidine, and spermine levels were reduced by 89, 52, and 43%, respectively, compared to those in control cells. The DAB treatment induced several ultrastructural alterations, which were primarily observed in the redox organelles termed hydrogenosomes. These organelles were progressively degraded, giving rise to large vesicles that displayed material immunoreactive with an antibody to beta-succinyl-coenzyme A synthetase, a hydrogenosomal enzyme. A protective role for polyamines as stabilizing agents in the trichomonad hydrogenosomal membrane is proposed.

Animals↗
PubMed2002

Polyamines regulate beta-catenin tyrosine phosphorylation via Ca(2+) during intestinal epithelial cell migration.

Polyamines are essential for early mucosal restitution that occurs by epithelial cell migration to reseal superficial wounds after injury. Normal intestinal epithelial cells are tightly bound in sheets, but they need to be rapidly disassembled during restitution. beta-Catenin is involved in cell-cell adhesion, and its tyrosine phosphorylation causes disassembly of adhesion junctions, enhancing the spreading of cells. The current study determined whether polyamines are required for the stimulation of epithelial cell migration by altering beta-catenin tyrosine phosphorylation. Migration of intestinal epithelial cells (IEC-6 line) after wounding was associated with an increase in beta-catenin tyrosine phosphorylation, which decreased the binding activity of beta-catenin to alpha-catenin. Polyamine depletion by alpha-difluoromethylornithine reduced cytoplasmic free Ca(2+) concentration ([Ca(2+)](cyt)), prevented induction of beta-catenin phosphorylation, and decreased cell migration. Elevation of [Ca(2+)](cyt) induced by the Ca(2+) ionophore ionomycin restored beta-catenin phosphorylation and promoted migration in polyamine-deficient cells. Decreased beta-catenin phosphorylation through the tyrosine kinase inhibitor herbimycin-A or genistein blocked cell migration, which was accompanied by reorganization of cytoskeletal proteins. These results indicate that beta-catenin tyrosine phosphorylation plays a critical role in polyamine-dependent cell migration and that polyamines induce beta-catenin tyrosine phosphorylation at least partially through [Ca(2+)](cyt).

Actin Cytoskeleton↗
PubMed2002

Effect of hindlimb suspension and clenbuterol treatment on polyamine levels in skeletal muscle.

Polyamines are unbiquitous, naturally occurring small aliphatic, polycationic, endogenous compounds. They are involved in many cellular processes and may serve as secondary or tertiary messengers to hormonal regulation. The relationship of polyamines and skeletal muscle mass of adductor longus, extensor digitorum longus, and gastrocnemius under unloading (hindlimb suspension) conditions was investigated. Unloading significantly affected skeletal muscle polyamine levels in a fiber-type-specific fashion. Under loading conditions, clenbuterol treatment increased all polyamine levels, whereas under unloading conditions, only the spermidine levels were consistently increased. Unloading attenuated the anabolic effects of clenbuterol in predominately slow-twitch muscles (adductor longus), but had little impact on clenbuterol's action as a countermeasure in fast- twitch muscles such as the extensor digitorum longus. Spermidine appeared to be the primary polyamine involved in skeletal muscle atrophy/hypertrophy.

Adrenergic beta-Agonists↗
PubMed2003

Polyamines as olfactory stimuli in the goldfish Carassius auratus.

Electrophysiological responses of goldfish olfactory receptor neurons (ORNs) and goldfish behavioral responses to polyamines were investigated in vivo. Electro-olfactogram (EOG) recordings indicated that polyamines (putrescine, cadaverine and spermine) are potent olfactory stimuli for goldfish with estimated electrophysiological thresholds of 10(-8)-10(-7) mol l(-1), similar to that for L-arginine, the most stimulatory amino acid. Although thresholds were similar, the magnitude of the EOG responses to intermediate (10(-5)-10(-4) mol l(-1)) and high (10(-3) mol l(-1)) concentrations of polyamines dwarfed the responses to amino acids and related single amine containing compounds (amylamine and butylamine). The EOG responses to 0.1 mmol l(-1) putrescine, cadaverine and spermine were, respectively, 4.2x, 4.3x and 10.3x the response of the standard, 0.1 mmol l(-1) L-arginine. Electrophysiological cross-adaptation experiments indicated that polyamine receptor sites are independent from those to L-amino acids (alanine, arginine, glutamate, lysine, methionine and ornithine), bile salts (sodium taurocholate and taurolithocholate), the single amine containing compounds (amylamine and butylamine) and ATP. Further, the cross-adaptation experiments revealed the existence of independent receptor sites for the different polyamines tested. Pharmacological experiments suggested that polyamine odorant transduction does not primarily involve the cyclic AMP and IP(3) second messenger pathways. Behavioral assays indicated that polyamines are attractants that elicit feeding behavior similar to that elicited by L-amino acids.

Amines↗
PubMed1999

Polyamine biosynthesis inhibitors alter protein-protein interactions involving estrogen receptor in MCF-7 breast cancer cells.

We investigated the effects of polyamine biosynthesis inhibition on the estrogenic signaling pathway of MCF-7 breast cancer cells using a protein-protein interaction system. Estrogen receptor (ER) linked to glutathione-S-transferase (GST) was used to examine the effects of two polyamine biosynthesis inhibitors, difluoromethylornithine (DFMO) and CGP 48664. ER was specifically associated with a 45 kDa protein in control cells. In cells treated with estradiol, nine proteins were associated with ER. Cells treated with polyamine biosynthesis inhibitors in the absence of estradiol retained the binding of their ER with a 45 kDa protein and the ER also showed low-affinity interactions with a number of cellular proteins; however, these associations were decreased by the presence of estradiol and the inhibitors. When samples from the estradiol+DFMO treatment group were incubated with spermidine prior to GST-ER pull down assay, an increased association of several proteins with ER was detected. The intensity of the ER-associated 45 kDa protein increased by 10-fold in the presence of 1000 microM spermidine. These results indicate a specific role for spermidine in ER association of proteins. Western blot analysis of samples eluted from GST-ER showed the presence of chicken ovalbumin upstream promoter-transcription factor, an orphan nuclear receptor, and the endogenous full-length ER. These results show that multiple proteins associate with ER and that the binding of some of these proteins is highly sensitive to intracellular polyamine concentrations. Overall, our results indicate the importance of the polyamine pathway in the gene regulatory function of estradiol in breast cancer cells.

Amidines↗
PubMed1999

Effects of methotrexate and cyclophosphamide on polyamine levels in various tissues of rats.

The effects of methotrexate (MTX) and cyclophosphamide (CYP) on body weight, organ weight, and the concentration of putrescine, spermidine, and spermine in 14 different tissues were measured in rats that had been given these compounds for 5 consecutive days. These three polyamines in both the thymus and spleen of rats treated with MTX and CYP showed a statistically significant decrease. Further, putrescine in the seminal vesicles, kidney, liver, and small intestine of MTX-treated rats, and in the prostate, seminal vesicles, kidney, heart, liver, small intestine, and lung of CYP-treated rats, spermidine in the prostate, seminal vesicles, testis, thymus, spleen, kidney, heart, small intestine, and skeletal muscle of CYP-treated rats, and spermine in the prostate, seminal vesicles, kidney, heart, small intestine, and stomach of CYP-treated rats showed statistically significant decreases. Recognition of the significance of polyamine levels and attention to their response in anti-cancer drug therapy may have clinical implications.

Animals↗
PubMed1995

Polyamines as biomarkers of cervical intraepithelial neoplasia.

Polyamines (putrescine, spermidine and spermine) play critical roles in cell growth and transformation. Ornithine decarboxylase (ODC), key enzyme in polyamine biosynthesis, is considered a putative protooncogene crucial to the regulation of cell growth and transformation. Cancer patients have elevated levels of polyamines in their physiological fluids compared to normal counterparts. alpha-Difluoromethylornithine (DFMO), a specific suicide inhibitor of ODC, exhibits antitumor and antimetastasis activities, and displays effectiveness in many carcinogen-induced animal chemoprevention models. Therefore, we are using DFMO in a chemoprevention trial for cervical intraepithelial neoplasia grade III (CIN III), and evaluating patients for changes in polyamine metabolism as an intermediate marker of DFMO effect. A preliminary study showed that several milligrams of abnormal cervical biopsy tissue contained detectable levels of ODC activity and polyamines. Additionally, the presence of cadaverine suggested bacterial contamination of these tissues. For this reason, normal and abnormal biopsies collected during colposcopy were rinsed prior to frozen storage. In most patients, abnormal tissue showed greater ODC activities and lower spermidine/spermine ratios than normal tissues. Patients are now being treated with de-escalating doses of DFMO (1-0.06 g/m2/day) for one month. To study the effect of DFMO in patients with CIN III, we are collecting blood and cervical tissue specimens to measure the following parameters: plasma DFMO, ornithine and arginine levels; plasma N1-acetylspermidine levels; erythrocyte (blood polyamine carrier) free polyamine levels; cervical tissue free polyamine levels; cervical tissue N1-acetylspermidine levels; and cervical tissue ODC activities. N1-acetylspermidine will be examined as this compound is known to exist primarily in tumor tissues, not in normal tissues. We therefore established a high-performance liquid chromatography method for N1-acetylspermidine. We expect to find that polyamines are effective markers in analyzing DFMO effects in this chemoprevention trial, thus functioning as pharmacodynamic parameters as well as biomarkers for transformation.

Biogenic Polyamines↗
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↗
PubMed1994

Kainate-induced seizure activity stimulates the polyamine interconversion pathway in rat brain.

Systemic injection of kainic acid in adult rat is accompanied by a large increase in the accumulation of acetylated derivatives of spermidine and spermine in the hippocampus and piriform cortex of animals pretreated with the polyamine oxidase inhibitor, MDL 72527. Furthermore, the activity of the enzyme spermine/spermidine acetyltransferase is increased at 8 and 16 h after kainate injection in piriform cortex and hippocampus. These results indicate that the polyamine interconversion pathway is rapidly activated in limbic areas following kainate-induced seizure activity, and suggest that this pathway might participate in the resulting neuronal damage.

Acetylation↗