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PubMed1992

Polyamine plasma levels and liver regeneration following partial hepatic resection in man.

Polyamines (putrescine, spermidine, and spermine) are widely distributed in animal and vegetal tissues, where their intracellular concentration strictly correlates with normal and pathological cell growth and protein synthesis. By means of a sensitive HPLC technique, the fasting plasma concentrations of polyamines were measured serially in 11 patients who underwent partial hepatic resection because of focal liver lesions. Samples were obtained before surgery and over the next 6 months, during hepatic regeneration. Liver volume was also measured by ultrasound on the basis of the 3 maximum diameters of the liver. From 2 to 4 weeks after surgery, plasma putrescine increased by a maximum of 78%, and spermidine by approximately 50%. No changes were observed in spermine levels. The spermidine/spermine ratio nearly doubled during liver regeneration. The volume of the liver decrease from 1505 [SD 236] ml to 743 [151] ml after resection, and returned to nearly normal values after 6 months (1231 [100] ml, p < 0.05 vs. basal values). The liver regeneration rate was highest 2-4 weeks after resection, and declined thereafter, when prevailing polyamine concentrations returned to normal. These data show that liver regeneration is accompanied by a significant increase in fasting putrescine and spermidine concentrations, which might be biochemical signals of active liver cell regeneration.

Adult↗

PubMed2006

Emerging concepts in targeting the polyamine metabolic pathway in epithelial cancer chemoprevention and chemotherapy.

The polyamines are important molecules governing cell proliferation, survival and apoptosis. Consistent with their elevated levels in cancer, they have been shown to mediate tumor promotion and progression. Cellular and tissue polyamine pools and metabolic flux are regulated by a number of processes. Neoplastic transformation is accompanied with an increase in biosynthesis, decreased catabolism and elevated uptake of exogenous polyamines. Effective strategies for cancer chemoprevention and chemotherapy, targeting the polyamine metabolic pathway will likely require a combination of agents acting at multiple sites of this pathway. Genetic variability affecting expression of the ornithine decarboxylase gene suggests an association between ODC expression and cancer risk, and prediction of response to treatment in certain epithelial cancers.

Antineoplastic Agents↗

PubMed1996

Effects of secretagogues on insulin biosynthesis and secretion in polyamine-depleted pancreatic beta-cells.

To extend previous observations on the importance of polyamines for glucose-stimulated insulinogenesis (N. Welsh and A Sjöholm. Polyamines and insulin production in isolated mouse pancreatic islets. Biochem. J. 252: 701-707, 1988), the impact of other secretagogues on insulin secretion of islets partially depleted in polyamines by selective inhibitors of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase was monitored. Glucose-sensitive, but not basal, insulin release was partially abolished in polyamine-deficient islets. Qualitatively similar impairments in insulin secretion were recorded when such islets were stimulated with nonglucidic nutrients (alpha-ketoisocaproic acid + L-glutamine), a cationic amino acid (L-arginine), activators of phospholipase C (carbachol) or protein kinase C (12-O-tetradecanoylphorbol 13-acetate), an adenosine 1', 5'-cyclic monophosphate-raising agent (forskolin), or a hypoglycemic sulfonylurea (glibenclamide). Additionally, glucose-responsive (pro)insulin biosynthesis was preferentially impeded in polyamine-deficient islets. It is concluded that polyamines act as permissive or stimulatory factors in insulin production and release. In addition, they seemingly do not act in an inhibitory manner on phospholipase C, protein kinase C, or Ca2+ flux into these islets, in contrast to reports in which insulinoma and other cells were used.

Adenosylmethionine Decarboxylase↗

PubMed1994

The autocrine regulatory effect of vasoactive intestinal peptide on the growth of human pancreatic carcinoma cells.

In the present study, the effects of VIP on the growth of two human pancreatic carcinoma cell lines PU-PAN-1 and PANC-1 were determined using tritiated thymidine incorporation. VIP receptors, intracellular cAMP and polyamines were investigated. The results indicated that VIP at a concentration of 10(-8) mol/L to 10(-7) mol/L can significantly stimulate the growth of PU-PAN-1 cells but not PANC-1 cells. This effect is dose-dependent and abolished by VIP receptor antagonist, [4-C1-Phe6, Leu17] VIP, suggesting VIP receptors in PU-PAN-1 cells may mediate this effect. VIP can markedly elevate the levels of intracellular cAMP and polyamines in PU-PAN-1 cells, indicating that the growth-promoting effect stimulated by VIP may be via a rapid increase in the biosyntheses of cAMP and polyamines. In addition, the VIP-antibody inhibited the growth of PU-PAN-1 cells in serum-free culture medium. The results above suggested that VIP has an autocrine regulatory effect on this pancreatic carcinoma cell line (PU-PAN-1).

Biogenic Polyamines↗

PubMed1997

Effects of novel spermine analogues on cell cycle progression and apoptosis in MALME-3M human melanoma cells.

On the basis of encouraging preclinical findings, polyamine analogues have emerged as a novel class of experimental antitumor agents. The spermine derivative N1,N11-diethylnorspermine (DE-333, also known as DENSPM) is currently undergoing Phase I clinical trials against solid tumors. A series of systematically modified DE-333 analogues differing in intra-amine carbon distances and in N-alkyl terminal substituents (i.e., methyl, ethyl, and propyl) were evaluated in MALME-3M human melanoma cells, a cell line known to be cytotoxically affected by DE-333 and especially responsive to analogue induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. Analogues accumulated to comparable intracellular concentrations and similarly affected cell growth with IC50 values in the 0.5-1.0 microM range. During prolonged incubations, diethyl and dipropyl analogues were cytotoxic, whereas two dimethyl analogues were cytostatic. Cell cycle analysis following treatment with the cytotoxic analogues revealed a prominent G1 block apparent as an accumulation of cells in G0/G1 and depletion of S-phase cells as well as a less restrictive G2 block. By contrast, cytostatic analogues incompletely arrested cells in G1, leaving a significant number of S-phase cells. Morphological and immunocytochemical analysis of detached cells revealed a far greater proportion of apoptotic cells with cytotoxic analogues than with cytostatic analogues. Although spermidine/spermine N1-acetyltransferase activity was differentially induced by the analogues, there was no obvious correlation with cell cycle effects. Overall, these data indicate a previously unrecognized combined effect of polyamine analogues on cell cycle progression and apoptosis. On the basis of structure-function relationships, these activities may be manipulated to optimize therapeutic efficacy.

Acetyltransferases↗

PubMed2001

Effects of DL111-IT or combined with RU486 on uterine polyamines biosynthesis in rats during early gestation.

DL111-IT, a non-hormonal contragestional agent, revealed synergistic effects in combination with mifepristone (RU486) in some species. The present study was undertaken to clarify the role of DL111-IT when used alone or plus RU486 on uterine polyamines biosynthesis, histologic alteration of decidual cells, and antifertility activity in rats. The levels of polyamines in pregnant rat uterus were determined by formed benzoyl chloride derivatives of polyamines for RP-HPLC. The results showed that all the treated groups including DL111-IT 2.8 mg. kg(-1). d(-1), RU486 3.0 mg. kg(-1). d(-1), and DL111-IT 0.56 mg. kg(-1). d(-1) plus RU486 0.6 mg. kg(-1). d(-1) caused 100% early pregnancy arrest. Uterine putrescine, spermidine, and spermine levels in comparison with vehicle control were declined significantly from d7 of gestation (1 day after treatment) to d9 or d14 (3 days or 8 days after treatment) by Duncan's multiple range test, and accompanied by histologic alterations, edema, degeneration and dissolution of decidual cells with nuclei indefinite in appearance on d8 of gestation (2 days after treatment). The combined administration at lower doses caused the most injury. The data verified that the decrease in uterine polyamine levels and subsequent decidual cells injuries were the critical role of early pregnancy arrest induced by DL111-IT or RU486. The two compounds used in combination with lower dosages revealed greatly synergistic effects.

Abortifacient Agents, Nonsteroidal↗

PubMed1996

Motor depressant effects of systemically administered polyamines in mice: involvement of central NMDA receptors.

The systemic administration of polyamines (s.c.) produced a dose-dependent motor depression. With high doses the depressant effect was long-lasting and the animals showed signs of toxicity. ED50 values for spermine, spermidine and putrescine were 38, 90 and 251 mg/kg respectively. The motor depression induced by the systemic administration of N-methyl-D-aspartate (NMDA; 25 mg/kg i.p.) was used as a model for studying the interactions between polyamines and the NMDA receptor. Results indicate that (1) the motor effects elicited by NMDA are very similar to those induced by polyamines at ED50 doses; (2) polyamines, even at non-active doses, potentiate the motor depressant effect induced by NMDA; (3) the NMDA receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801; 0.5 mg/kg i.p.), abolishes the depressant effect elicited by NMDA and by polyamines, even at toxic doses; (4) amphetamine (1.5 mg/kg i.p.) does not counteract the motor depressant effects of NMDA or polyamines. On the other hand, the adenosine receptor antagonist, theophylline (30 mg/kg i.p.), counteracts NMDA- but not polyamine-induced motor depression. The concentration of polyamines in the brain is modified after their systemic administration at high doses and at the ED50 dose of putrescine. In conclusion, the data suggest that the NMDA receptor could be a target mediating the motor effect elicited by polyamines. They also show that the quantitative analysis of the motor effects elicited by non-convulsant doses of NMDA might be a powerful tool for studying in vivo the interaction between neurotransmission systems involved in the regulation of motor activity.

Amphetamine↗

PubMed2003

Polyamines as modifiers of genetic risk factors in human intestinal cancers.

Polyamines are downstream mediators of genetic risk factors in human intestinal cancers. The adenomatous polyposis coli (APC) tumour-suppressor gene, which is mutated in essentially all human colon cancers, regulates the expression of several e-box transcription factors. These factors, in turn, regulate the transcription of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. The Kirsten ras ( K-ras ) oncogene regulates the expression of several genes, including suppressing the expression of peroxisomal proliferator-activated receptor gamma (PPARgamma). This PPAR, in turn, activates the expression of the spermidine/spermine-N(1)-acetyltransferase (SSAT), the first enzyme in polyamine catabolism. The non-steroidal anti-inflammatory drug (NSAID) sulindac induces the transcription of SSAT via activation of PPARgamma. Inactivation of the APC tumour-suppressor gene, and the activation of K-ras, have a combined effect on increasing tissue polyamine contents due to increased synthesis and decreased catabolism of the polyamines. Pharmacological strategies for suppressing ODC (e.g. the enzyme-activated inhibitor alpha-difluoromethylornithine) and activating SSAT (e.g. NSAIDs) are potent inhibitors of intestinal carcinogenesis in rodent models. Clinical trials combining these classes of agent in humans with risk factors for colon cancer are in progress.

Antineoplastic Agents↗

PubMed2001

Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity.

Macrophages use L-arginine to synthesize nitric oxide (NO) and polyamines through the inducible NO synthase (iNOS) and arginase, respectively. The released NO contributes to the tumoricidal activity of macrophages, whereas polyamines may promote the growth of tumor cells. Both the tumoricidal and growth-promoting activities from macrophages have been reported; however, the underlying mechanisms for switching between this dual function of macrophages remain unclear. Here, we test the hypothesis that arginase participates in the switching between the cytotoxic and growth-promoting activities of macrophages toward tumor cells. To alter arginase activity in macrophages, cells (murine macrophage cell line J774A.1) were transfected with the rat liver arginase gene or treated with an arginase inhibitor, L-norvaline. The effects of macrophage arginase activity on the growth-promoting and cytotoxic activities of macrophages toward breast tumor cells (ZR-75-1) were investigated in a coculture system. The results demonstrated that overexpression of arginase in macrophages enhanced L-ornithine and putrescine production and consequently promoted tumor cell proliferation. This proliferative effect was down-regulated by the arginase inhibitor L-norvaline. Furthermore, increases in arginase activity also attenuated NO production by the lipopolysaccharide-activated macrophages and thus reduced the cytotoxic effect on cocultured tumor cells. Inhibiting arginase activity by L-norvaline effectively reversed the suppression of NO-mediated tumor cytotoxicity. Together, these results suggest that arginase induction in macrophages can enhance tumor cell growth by providing them with polyamines and suppress tumor cytotoxicity by reducing NO production. It appears that L-arginine metabolism through the arginase and iNOS pathways in macrophages can have very different influences on the growth of nearby tumor cells depending on which pathway is prevailing.

Adenocarcinoma↗

PubMed1991

Ornithine decarboxylase activity and polyamine content in adenocarcinomas of human stomach and large intestine.

Ornithine decarboxylase (ODC) activity and differential polyamine composition have been studied in macroscopically normal mucosa, adjacent mucosa, and neoplastic tissue of 95 patients with adenocarcinomas of stomach and large intestine. In tumors, we found increased ODC activity and polyamine content as compared with surrounding mucosa. ODC activity in macroscopically normal tissue of patients with tumors of stomach and large intestine increased as the disease progressed. An inverse relationship was observed between ODC activity in adenocarcinomas and differentiation.

Adenocarcinoma↗

PubMedDate not supplied

Duodenogastric reflux, histology and cell proliferation of the gastric mucosa before and six months after cholecystectomy.

In order to evaluate the effects that an increase in duodenogastric reflux (DGR) has on the mucosal cell proliferation of the non-operated stomach, we made a prospective study on 13 patients (9 female and 4 male, mean age 52 years) both before and 6 months after cholecystectomy, an operation which determines a significant increase in DGR with an intact pyloric sphincter. DGR was evaluated by measuring total intragastric bile acids (dosed by an enzymatic method), and single intragastric bile acids (dosed by High Performance Liquid Chromatography) and it was expressed as Fasting Bile Reflux (FBR) in mumol/h. Gastric cell proliferation was evaluated by measuring (by High Performance Liquid Chromatography) polyamine (putrescine, spermidine and spermine) levels in biopsy specimens taken from the antrum and gastric body. The histology of the antrum and gastric body was also evaluated. After cholecystectomy, there was a significant increase in DGR (delta = 39.23 mumol/h, 95% C.L. 11.69-136.22, sign-test for matched pairs p = 0.0003). The tissue concentration of putrescine in the antrum increased significantly (delta = 8.36 mumol/g of tissue, 95% C.L. 0.34-18.01, sign-test for matched pairs p = 0.013) and there was a worsening of histological findings in the antrum (preoperative chronic atrophic gastritis rate 38.5%, postoperative 69%). In the body there were no significant variations either in polyamine levels or in histology. The increase in DGR and in putrescine concentrations in the antrum were associated negatively (Spearman's rank -0.64, 95% C.L. -0.88 to -0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2000

Mixed-ligand complexes of copper(II) ions with AMP and CMP in the systems with polyamines and non-covalent interaction between bioligands.

The occurrence of non-covalent interactions and formation of molecular complexes between adenosine 5'-monophosphate (AMP) or cytidine 5'-monophosphate (CMP) and the polyamines, putrescine, 1,7-diamino-4-azaheptane (3,3-tri), spermidine and 1,11-diamino-4,8-diazaundecane (3,3,3-tet), were detected in metal-free systems. The stoichiometric composition of the adducts and their stability constants were determined on the basis of computer analysis of the titration data, taking into account the fact that the acid-base properties of the system change as a result of these interactions. Spectral analysis allowed an identification of the interaction centers in the adducts as protonated amine groups of polyamines, phosphate groups as well as nitrogen atoms of high electron density from nucleotides. Unexpectedly, no participation of the phosphate group from AMP in the formation of molecular complexes with tetramine-3,3,3-tet was detected. The stoichiometric composition and stability constants of mixed-ligand complexes in the systems of Cu(II) with AMP or CMP and polyamines were obtained. Analysis of the results of equilibrium studies and 13C, 31PNMR, UV-Vis, IR and EPR data permitted determination of the mode of coordination. In the systems with metal ions, the formation of molecular complexes Cu(CMP)H4(3,3-tri) was found, apart from heteroligand complexes of the MLL' and MLL'Hx type. In protonated complexes the occurrence of non-covalent interactions leading to stabilization of the coordination compounds was observed. The differences in the character of coordination biogenic amines and their biologically inactive analogs were identified.

Adenosine Monophosphate↗

PubMed1989

Polyamines of sulfur-dependent archaebacteria and their role in protein synthesis.

Several strains of the sulfur-dependent archaebacterium, Sulfolobus, were analyzed for their polyamine content. Caldine (norspermidine), spermidine, and thermine were found to be major components in all of the cells tested. The most abundant polyamine in all cultures examined was spermidine. The Langworthy strain had the highest spermine content, whereas S. acidocaldarius strain no. 7 was devoid of this polyamine. Cultures of strain no. 7 grown at 70 degrees C were rich in spermidine and caldine (triamines) and the thermine: spermidine ratio was much lower than that of cultures grown at 78 degrees C. Equal amounts of thermine and spermidine were present in strain DSM 1616. Preincubation of Langworthy strain extracts at 10 degrees C did not overcome the requirement for polyamines in protein synthesis. Putrescine exerted a concentration-dependent inhibition of the spermine-induced stimulation of protein synthesis at 70 degrees C. Increasing concentrations (6 and 9 mM) of spermine and thermine progressively inhibited poly(U)-dependent phenylalanine incorporation at 45 degrees C to about the same extent, whereas the same concentrations of these polyamines had little effect on the reaction at 70 degrees C. Although 3 mM spermine had only a slight stimulatory effect on the attachment of phenylalanine to tRNA at 65 degrees C, this polyamine had a pronounced effect on the formation of 70S ribosomes in a standard buffer containing 10 mM Mg2+. Increasing the Mg2+ concentration to 30 mM in the absence of spermine was even more effective in causing the reassociation of subunits to form 70S particles.

Amino Acids↗

PubMed2002

A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons.

AMPA receptors mediate most of the fast excitatory neurotransmission in the brain, and those lacking the glutamate receptor 2 (GluR2) subunit are Ca(2+)-permeable and expressed in cortical structures primarily by inhibitory interneurons. Here we report that synaptic AMPA receptors of excitatory layer 5 pyramidal neurons in the rat neocortex are deficient in GluR2 in early development, approximately before postnatal day 16, as evidenced by their inwardly rectifying current-voltage relationship, blockade of AMPA receptor-mediated EPSCs by external and internal polyamines, permeability to Ca(2+), and GluR2 immunoreactivity. Overall, these results indicate that neocortical pyramidal neurons undergo a developmental switch in the Ca(2+) permeability of their AMPA receptors through an alteration of their subunit composition. This has important implications for plasticity and neurotoxicity.

Aging↗

PubMed1988

Neonatal central catecholaminergic lesions with intracisternal 6-hydroxydopamine: effects on development of presynaptic and postsynaptic components of peripheral sympathetic pathways and on the ornithine decarboxylase/polyamine system in heart, lung and kidney.

Peripheral sympathetic neurons are thought to provide trophic regulatory signals for development of adrenergic target tissues. In the current study, we destroyed central catecholaminergic pathways in the neonatal rat by intracisternal administration of 6-hydroxydopamine, which compromises sympathetic tone without ablating peripheral nerve terminals. Measurements of norepinephrine levels and turnover confirmed the effectiveness of the treatment in projections to heart, lung and kidney. The impairment of sympathetic tone was associated with a deficit in cardiac beta adrenergic receptor binding capabilities; in contrast, binding sites in the lung were unaffected and renal receptors were up-regulated. Similarly, intracisternal administration of 6-hydroxydopamine produced tissue-selective alterations in ornithine decarboxylase activity and levels of the polyamines. These results support the view that neural activity exerts an influence on the biochemical development of sympathetic target tissues; however, other trophic factors may derive from the presence of intact nerve terminals themselves, as distinct from activity.

Animals↗

PubMed2001

The effect of polyamine biosynthesis inhibition on growth and differentiation of the phytopathogenic fungus Sclerotinia sclerotiorum.

We studied the effects of several polyamine biosynthesis inhibitors on growth, differentiation, free polyamine levels and in vivo and in vitro activity of polyamine biosynthesis enzymes in Sclerotinia sclerotiorum. Alpha-Difluoromethylornithine (DFMO) and alpha-difluoromethylarginine (DFMA) were potent inhibitors of mycelial growth. The effect of DFMO was due to inhibition of ornithine decarboxylase (ODC). No evidence for the existence of an arginine decarboxylase (ADC) pathway was found. The effect of DFMA was partly due to inhibition of ODC, presumably after its conversion into DFMO by mycelial arginase, as suggested by the high activity of this enzyme detected both in intact mycelium and mycelial extracts. In addition, toxic effects of DFMA on cellular processes other than polyamine metabolism might have occurred. Cyclohexylamine (CHA) slightly inhibited mycelial growth and caused an important decrease of free spermidine associated with a drastic increase of free putrescine concentration. Methylglyoxal bis-[guanyl hydrazone] (MGBG) had no effect on mycelial growth. Excepting MGBG, all the inhibitors strongly decreased sclerotial formation. Results demonstrate that sclerotial development is much more sensitive to polyamine biosynthesis inhibition than mycelial growth. Our results suggest that mycelial growth can be supported either by spermidine or putrescine, while spermidine (or the putrescine/spermidine ratio) is important for sclerotial formation to occur. Ascospore germination was completely insensitive to the inhibitors.

Arginine↗

PubMed2003

Polyamines and their role in human disease--an introduction.

The naturally occurring polyamines are found in all living cells, where they fulfil a number of critical functions in relation to cell growth. The quest to identify these functions has been the subject of five independent colloquia hosted by the Biochemical Society and today still occupies several hundred scientists across Europe, the U.S.A. and Japan.

Antineoplastic Agents↗

PubMed2006

Characterization and a role of Pseudomonas aeruginosa spermidine dehydrogenase in polyamine catabolism.

Pseudomonas aeruginosa PAO1 has two possible catabolic pathways of spermidine and spermine; one includes the spuA and spuB products with unknown functions and the other involves spermidine dehydrogenase (SpdH; EC 1.5.99.6) encoded by an unknown gene. The properties of SpdH in P. aeruginosa PAO1 were characterized and the corresponding spdH gene in this strain identified. The deduced SpdH (620 residues, calculated Mr of 68,861) had a signal sequence of 28 amino acids at the amino terminal and a potential transmembrane segment between residues 76 and 92, in accordance with membrane location of the enzyme. Purified SpdH oxidatively cleaved spermidine into 1,3-diaminopropane and 4-aminobutyraldehyde with a specific activity of 37 units (mg protein)(-1) and a Km value of 36 microM. The enzyme also hydrolysed spermine into spermidine and 3-aminopropanaldehyde with a specific activity of 25 units (mg protein)(-1) and a Km of 18 microM. Knockout of spdH had no apparent effect on the utilization of both polyamines, suggesting that this gene is minimally involved in polyamine catabolism. However, when spdH was fused to the polyamine-inducible promoter of spuA, it fully restored the ability of a spuA mutant to utilize spermidine. It is concluded that SpdH can perform a catabolic role in vivo, but P. aeruginosa PAO1 does not produce sufficient amounts of the enzyme to execute this function.

Biogenic Polyamines↗