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PubMed1982

Polyamines and membrane proteins in sickle cell disease.

The polyamines, putrescine, spermidine, and spermine have been implicated in cellular growth and membrane stabilization. We have shown that RBC stroma and lysate polyamines are significantly elevated in sickle cell disease (SS and SC) relative to controls (AA). The crude spectrin fraction of the red cell stroma has associated with it a large fraction of the total stroma polyamines, suggesting that the polyamines in the stroma are preferentially bound to spectrin. The high levels of polyamines associated with the spectrin of young and ISC's relative to normal may contribute to an alteration of the physical-chemical properties of the sickle RBC membrane. Spermine levels were high in the SS lysates but not detectable in SC or AA lysates. Levels in SC patients were intermediate. In preliminary experiments using washed red cells obtained from SS and AA subjects, there was extensive incorporation of 14C putrescine into red cell protein. Labelled N-(gamma-glutamyl) putrescine was isolated, consistent with covalent binding of the polyamines to protein.

Anemia, Sickle Cell↗
PubMed1981

[The clinical significance of determination of red blood cell and urinary polyamines in gynecologic malignancy (author's transl)].

The polyamines spermidine (spd) and spermine (spm), and their diamine precursor, putrescine (put) were separately determined in red blood cells (RBC) and 24-hour urine samples of gynecologic malignant and non-malignant cases using high-pressure liquid chromatography (HPLC) technique. The results are as follows: 1) Patients with malignancy (49 cases) had the polyamine levels of RBC-spd; 5.85 +/- 3.32 (mean +/- SD), RBC-spm; 7.00 +/- 5.53 (nmol/ml packed RBC), urinary put; 3.92 +/- 4.13, urinary spd; 2.17 +/- 1.74 (mg/day) in pre-therapeutic state. These levels were greatly higher than those of control cases. 2) The diagnostic rate was 100% in the fourth stage of uterine cervical cancer, and 80% in the recurrent cases. 3) Patients with long-term abnormal polyamine levels had the tendency of poor prognosis. 4) In many cases, RBC polyamines and urinary polyamines showed somewhat different fluctuations in the course of treatment. In conclusion, it is suggested that the measurement of polyamines is very useful in the diagnosis of progressive cases and recurrent cases, and can be helpful in the evaluation of therapeutic effects and prognosis.

Chromatography, High Pressure Liquid↗
PubMed1980

Change of polyamine content in mouse skin by leupeptin, a protease inhibitor, during early stage of tumorigenesis.

The effect of a microbial protease inhibitor, leupeptin, on the content of polyamine in the mouse skin was examined during the early stage of tumorigenesis induced by a single application of 7,12-dimethylbenz[a]anthracene (DMBA) and repeated application of croton oil thereafter. Polyamine content in the skin was measured at 3, 5, 7, and 9 weeks during tumorigenesis. The mice with no visible tumor were selected for measurement of polyamine content at 9 weeks. Mice were left untreated for at least 1 week before measurement of polyamine. Polyamine in the skin was extracted with ice-cold 0.4N HClO4 and separated into putrescine, spermidine, and spermine fractions through CM-cellulose column. Polyamine concentration was determined by fluorometry with fluorescamine. Group A mice painted with croton oil 3 times a week did not develop tumors. Group B mice painted with a single DMBA developed skin tumors, and group C mice painted with a single DMBA and croton oil 3 times a week showed higher development of skin tumors than group B. Group D mice treated as group C and then painted with leupeptin about 2 hr after croton oil treatment. Animals in groups B, C, and D had higher spermidine content as group A at 3 and 5 weeks. Content of spermidine in group B decreased at 7 and 9 weeks compared with group C which had a high content throughout the time tested. Leupeptin treatment in group D inhibited spermidine content in the skin after 7 weeks without affecting until 5 weeks.

Animals↗
PubMed1995

Polyamine depletion-mediated effects on murine odontogenesis are dependent on tooth developmental stage and culture conditions.

Polyamines are known to play a central role in processes such as growth and development. Virtually nothing is known about their importance in tooth development, an attractive and frequently used experimental model for studies of developmental processes. A polyamine-depleted state was created in tooth cells in an organ culture system. First lower molar germs from 16-and 17.5-day old mouse fetuses were used. alpha-difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were used to deplete the cells from their polyamine content. Polyamine interconversion and catabolism were prevented by aminoguanidine sulfate (AG). In day-16 germs cultured in serum-containing medium, DFMO reduced the frequency of cycling cells as shown by [3H]thymidine incorporation, and induced a delay of odontoblast differentiation of about 24 h. Under the same conditions, MGBG induced an arrest of histo-morphogenesis, correlated to a significant decrease in the rate of cell proliferation. Addition of polyamines prevented DFMO- and MGBG-induced delay of tooth differentiation. Interestingly, MGBG did not delay the terminal differentiation of odontoblasts and ameloblasts in cultured day-17.5 molars; in these, cells at the tip of the cusps are only a few hours before their withdrawal from the cell cycle. In serum-deprived medium, dental cytodifferentiations did not occur. Addition of putrescine or spermidine to serum-free media, however, allowed for tooth morphogenesis and cytodifferentiation. Tooth explants in a serum-deprived medium reacted to DFMO in a cytocidal fashion, whereas MGBG showed only a mild toxicity in some cell types. Addition of putrescine to DFMO-containing medium prevented its cytotoxic effect. Addition of spermidine to MGBG-containing medium not only prevented its mild toxicity but also allowed for predentin secretion by differentiated odontoblasts. The results are discussed with regard to the well-established developmental events of tooth germs cultured in vitro and with respect to present knowledge of polyamine metabolism and their involvement in cellular processes.

Animals↗
PubMed1976

Polyamine stimulation and cation requirements of rabbit liver tRNA nucleotidyltransferase.

We have examined the cation requirements of rabbit liver tRNA nucleotidyltransferase. The enzyme had an absolute requirement fo a divalent cation which could be satisfied by Mg2+, Mn2+ or Co2+. In contrast to the Escherichia coli enzyme, we have found no evidence to implicate Zn2+ in the action of rabbit liver tRNA nucleotidyltransferase. We have also identified a second cation requirement which was satisfied by divalent or monovalent cation or polyamines. The polyamines, spermine and spermidine, were most effective leading to 3-fold higher rates of nucleotide incorporation than could be obtained at any concentration of the other cations. However, the polyamines were not an absolute requirement for enzyme activity. The polyamine stimulation of tRNA nucleotidyltransferase was not due to alteration of the pH or ionic strength of the reaction mixture or reactivation of denatured tRNA or enzyme. Polyamines also had no effect on the apparent Km values of the substrates. Spermine increased the specificity of the enzyme for tRNA substrates and also inhibited the reverse action. Our results suggest that polyamines may be the normal counterions for tRNA in vivo, and that they affect the rate-limiting step in tRNA nucleotidyltransferase catalysis.

Animals↗
PubMed1995

Role of polyamines in hypertension induced by angiotensin II.

OBJECTIVE: The aim was to investigate the involvement of polyamines in the development of cardiovascular hypertrophy in a rat angiotensin II infusion model of hypertension. METHODS: Rats were chronically infused with a low dose of angiotensin II (83 ng.min-1.rat-1) or vehicle by osmotic minipumps. The polyamine content of the cardiovascular organs and liver was measured by HPLC, and the blood pressure of conscious rats was determined by a tail cuff method. The mesenteric arterial beds were perfusion fixed in situ and medial and luminal cross sectional areas were determined by computer assisted planimetry. Cardiac hypertrophy was assessed by determination of ventricular:body weight ratios. RESULTS: Angiotensin II infusion caused an increased concentration of polyamines in the ventricles and aorta within hours of beginning the infusion, and within days in the mesenteric arteries. Polyamine content of the liver was unaffected. Hypertrophy of the myocardium and mesenteric arteries in association with the increased blood pressure was evident. CONCLUSIONS: A low dose of angiotensin II stimulates an early biochemical marker of growth, the polyamines, in cardiovascular tissues but not in the liver. The increase in tissue polyamines is associated with cardiovascular hypertrophy and the development of hypertension.

Angiotensin II↗
PubMed1994

[The determination of polyamines in tumors of the maxillofacial area].

Putrescine, spermidine and spermine are polyamines deriving from ornithine. These are vital molecules for cell duplication processes; in fact, enzyme inhibitors responsible for synthesis are able to block cell multiplication. It is interesting to observe that there is an increased concentration of the polyamines and enzymes responsible for synthesis in solid tumours in man and in biological fluids in subjects carrying tumours. The authors assayed the polyamine concentration in tumour tissue taken from 10 cases of parotid carcinoma, noting a considerable increase in their levels compared to healthy control tissues. The hypothesis of being able to use the level of polyamines present in biological fluids in order to make an early diagnosis of tumours has now been definitively abandoned, both due to the scarce specificity and sensitivity of the available methods and due to the fact that increased polyamine concentrations were also found in physiological conditions and in the presence of non-tumour diseases; however, it is now being examined whether it would be possible to use polyamine levels to assess the degree of biochemical tumour malignancy or to evaluate the response to surgical or pharmacological treatment in patients with malignant tumours.

Carcinoma↗
PubMed1994

Polyamine inhibition of transbilayer movement of plasma membrane phospholipids in the erythrocyte ghost.

The resting plasma membrane of circulating blood cells demonstrates an asymmetric distribution of the phospholipid classes across the bilayer that is altered during cellular activation. To better understand the mechanisms governing transbilayer distribution of phospholipids, studies were conducted using the erythrocyte ghost, in which plasma membrane leaflet distribution of phospholipids can be readily probed. Preparation of ghosts by hypotonic lysis at increasingly high dilution markedly enhanced (up to 10-fold) calcium-induced (50-500 microM) transbilayer movement of phospholipids. The enhanced transbilayer movement was assessed by translocation of exogenously added sn-2-[6[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]caproyl]-labeled phosphatidylcholine and phosphatidylserine from the plasma membrane outer leaflet to the inner leaflet and vice versa, as well as transbilayer movement of endogenous phosphatidylserine to the outer leaflet. It was found that phospholipid movement was bidirectional and also nonspecific with regard to polar head group. It was further demonstrated that preparation of ghosts at increasing dilution resulted in depletion of cellular polyamines and that physiologic replenishment of spermine, and to a lesser extent spermidine, resulted in significant inhibition (50 and 25%, respectively) of transbilayer movement of phospholipids. Replenishment of other di- and polyamines demonstrated that inhibition was not simply dependent on total cationic charge but rather on charge density and suggestive of specific interaction of the polyamines, particularly spermine, with the plasma membrane. As most cells demonstrate both a high degree of regulation in maintenance of polyamine levels and the means for facile shifts within cellular polyamine pools, it is suggested that loss of membrane asymmetry during cellular activation may be mediated in part through enhanced transbilayer movement of phospholipids due to altered polyamine-membrane associations.

4-Chloro-7-nitrobenzofurazan↗
PubMedDate not supplied

Difluoromethylornithine and ethylglyoxal bis(guanylhydrazone) as inhibitors of human renal carcinoma cell proliferation and polyamine metabolism.

The significance of the polyamines putrescine, spermidine and spermine for the neoplastic proliferation of the human renal carcinoma cell line ACHN was investigated. For this purpose cells were cultured in vitro for 4 days with or without the addition of pathway inhibitors of polyamine biosynthetic enzymes. It was found that treatment of ACHN cells with the specific ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) resulted in profound decreases of ODC activity, polyamine content and cell proliferation rates along with a compensatory increase in S-adenosylmethionine decarboxylase (SAMDC) activity. Ethylglyoxal bis(guanylhydrazone) (EGBG), a SAMDC inhibitor, evoked a similar reduction of cell proliferation and contents of spermidine and spermine. EGBG also seemed to stabilize SAMDC, as evidenced by a highly enhanced SAMDC activity during enzyme assays in the absence of the inhibitor. Furthermore, EGBG treatment caused on activation of ODC and a subsequent build-up of putrescine. The impact on polyamine contents and proliferation rates were synergistic when the inhibitors were used in combination. None of the inhibitors alone exerted a cytocidal activity. It is concluded that polyamines may be implicated in the regulation of the neoplastic proliferation of cultured human renal carcinoma cells and that polyamine synthesis inhibitors may prove valuable in clinical treatment of this disease.

Cell Division↗
PubMed1993

Spermidine/spermine N1-acetyltransferase--the turning point in polyamine metabolism.

Polyamines are thought to have several vital roles in cell growth and differentiation. The highly regulated polyamine metabolic pathway provides cells with the ability to finely control the intracellular concentration of these ubiquitous polycations. Although earlier studies of regulation of polyamine content were concentrated on the biosynthetic reactions, recently the importance of the catabolic processes, particularly the highly regulated acetylation step in polyamine degradation, has become apparent. This work has led to an understanding of how a cell may, in a tightly controlled manner, facilitate the breakdown, excretion, cycling, and/or intracellular shuttling of the polyamines. This myriad of possibilities appears to be regulated initially at a single rate-limiting enzymatic step, the N1-acetylation of spermidine or spermine, by spermidine/spermine N1-acetyltransferase (SSAT). Recent cloning of the human SSAT gene has facilitated a more detailed study of this enzyme. SSAT appears to have a role in the determination of tumor sensitivity to a new class of antineoplastic agents. The further study of SSAT and the associated polyamine metabolism should provide a better understanding of the regulation and function of these cations.

Acetylation↗
PubMed1995

DNA methylation and polyamines in embryonic development and cancer.

Mammalian DNA contains relatively large amounts of a modified base, 5-methyl-cytosine (m5C). Methylation of cytosine is catalyzed by DNA(cytosine-5)methyltransferase (DNA MTase). DNA methylation seems to play an important role in the regulation of gene expression during development. Thus, m5C may inhibit transcription by preventing the binding of transcription factors and/or by altering chromatin structure. The DNA methylation patterns of the male and female pronuclei are erased in the morula and early blastula, and when the blastocyst forms, most of the DNA has become demethylated. Following implantation, however, there is a surge of de novo methylation affecting the entire genome, and already by gastrulation DNA is methylated to an extent characteristic of that of the adult animal. During subsequent development, tissue-specific genes undergo programmed demethylation, which may cause their activation. Site-directed mutagenesis of the DNA MTase gene, has recently shown that DNA methylation is absolutely required for normal development of the early mouse embryo. DNA methylation and polyamine synthesis depend on a common substrate, S-adenosylmethionine (AdoMet). As a consequence, changes in cellular polyamine levels may affect the degree of DNA methylation. When the first step in the polyamine biosynthetic pathway is blocked, F9 teratocarcinoma stem cells accumulate large amounts of decarboxylated AdoMet, the aminopropyl group donor in polyamine synthesis, and go through terminal differentiation into parietal endoderm cells. The accumulation of decarboxylated AdoMet is a direct consequence of the polyamine-depleted state of the cell. Although the decarboxylated AdoMet molecule contains a methyl group, it does not act as a methyl group donor in DNA methylation. Instead it acts as a competitive inhibitor of DNA MTase. A consequence of polyamine depletion is therefore genome-wide loss of DNA methylation due to insufficient maintenance methylation during successive rounds of DNA replication. Our recent finding that prevention of the accumulation of decarboxylated AdoMet counteracts the differentiative effect lends further support to the hypothesis proposed.

5-Methylcytosine↗
PubMed1995

Polyamines enhance calcium pyrophosphate dihydrate crystal dissolution.

OBJECTIVE: Alkaline phosphatase (ALP), an enzyme with pyrophosphatase (PP(i)ase) activity, can dissolve calcium pyrophosphate dihydrate (CPPD) crystals. We investigated the CPPD crystal dissolution activity of polyamines, substrates known to enhance PP(i)ase activity. METHODS: An in vitro model system for crystal enzyme interaction was used to assess CPPD crystal dissolution both biochemically and morphologically. RESULTS: We demonstrated biochemically and morphologically that polyamines such as spermine and spermidine can enhance CPPD crystal dissolution activity of ALP. Polyamines enhanced ALP induced CPPD crystal dissolution and ALP PP(i)ase activity differentially. By scanning electron microscopy, we observed that polyamines enhanced dissolution stereoselectively at the small end faces (optical 010 faces) of CPPD crystals, indicated by the presence of etch pits. CONCLUSION: Polyamines assist ALP to promote the stereoselective dissolution of CPPD crystals. In addition to implications for CPPD crystal dissolution, as ALP is present intracellularly, these studies suggest that polyamines and ALP have synergistic effects when ALP PP(i)ase activity is required for intracellular energy metabolism.

Alkaline Phosphatase↗
PubMedDate not supplied

[Polyamine evaluation in serum and erythrocytes of pediatric patients with neoplasms].

BACKGROUND: As previous studies demonstrated, free polyamines (putrescine, spermidine and spermine) are increased in neoplastic tissue and in body fluid (blood, urine and spinal fluid) of patients with tumours in various localization. In pediatric oncology, there aren't many specific markers useful to screen subjects at risk of developing cancer or to follow-up after treatment. For these reasons, polyamines' levels in plasma and erythrocytes have been evaluated in three groups of patients: healthy, with acute leukemia and with solid tumour. METHODS: Polyamines' content has been determined on samples of blood, previously dansylated, by HPLC (high performance liquid chromatography). RESULTS: The results of this study show that putrescine is decreased in plasma of patients with acute leukemia and with solid tumours. The difference, even if more important in subjects with leukemia, is significant in both groups. Spermidine instead, shows an increase, but only in patients with solid tumour. Erythrocyte assays reveal a significant decrease of spermidine in subjects with acute leukemia with consequent inversion of spermidine/spermine ratio. In erythrocytes there aren't any other significant changes in relation to the levels observed in healthy patients. Polyamine assay, especially that of putrescine and spermidine in plasma, could be propounded as a marker for pediatric neoplasms. CONCLUSIONS: Moreover, as it is well-known, pediatric neoplasms lead to alterations of polyamine metabolism, because the synthesis and catabolism of these molecules is closely involved in tumoral growth. Consequently, inhibitors of polyamine synthesis could be used with success in antineoplastic chemotherapy.

Adolescent↗
PubMedDate not supplied

Effects of suramin on polyamine metabolism in B16 murine melanoma cells.

Polyamines and their biosynthetic enzymes, such as ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), are crucial for normal and neoplastic cell growth and differentiation. Suramin inhibits the growth of several tumor cells by affecting various intracellular targets, but its effects on polyamines are not known. In this study, the effects of suramin on some parameters of polyamine metabolism in B16 melanoma cells were investigated in vitro. Suramin increased cellular ODC activity and ODC mRNA levels, whereas the drug was directly inhibitory to the enzyme. AdoMetDC was not affected. Cellular putrescine levels were enhanced by suramin, whereas spermidine and spermine pools were unaltered. Cells cultured in the presence of suramin showed decreased cellular polyamine transport, but no direct inhibitory effect on the polyamine transporter could be found. Fluorescence spectroscopy demonstrated a direct interaction between suramin and spermine. It may be concluded that suramin affects polyamine metabolism, and that its effects in some respects are opposite to those of alpha-difluoromethylomithine (DFMO), a specific inhibitor of ODC.

Adenosylmethionine Decarboxylase↗
PubMed1998

Streptomycin bactericidal action is dependent on polyamine endogenous levels in E. coli.

E. coli polyamine-supplemented and depleted cultures showed an important difference in survival to streptomycin; the bactericidal effect of the antibiotic was remarkably higher in cells with normal levels of polyamines. Similar results were observed with kanamycin. Analysis of the polyamine-containing cells pulse-labelled with 35S-methionine during streptomycin action indicated that the amounts of newly-synthesized peptides in various subcellular fractions was different from the amounts formed in the untreated controls; the most dramatic change was found in the residual particulate fraction where the antibiotic treatment caused a 3-fold increase of radioactive proteins. On the contrary, equivalent amounts of labelled peptides were detected in the different fractions prepared from polyamine-depleted bacteria incubated with or without antibiotic. In this case the corresponding residual fraction was only slightly increased. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the different fractions showed some changes elicited by streptomycin in the protein patterns of polyamine-containing bacteria, especially in the residual fractions. The electrophoretic profile corresponding to deprived cells was very similar in all cases. The role of polyamines in the conformation of the outer membrane and in the correct assembly of ribosomes is discussed on account of the enhancing effect of these polycations on the bactericidal action of streptomycin.

Anti-Bacterial Agents↗
PubMed1998

Activity-dependent modulation of glutamate receptors by polyamines.

The mechanisms by which polyamines block AMPA and kainate receptors are not well understood, but it has been generally assumed that they act as open-channel blockers. Consistent with this, voltage-jump relaxation analysis of GluR6 equilibrium responses to domoate could be well fit, assuming that spermine, spermidine, and philanthotoxin are weakly permeable open-channel blockers. Analysis of rate constants for binding and dissociation of polyamines indicated that the voltage dependence of block arose primarily from changes in koff rather than kon. Experiments with changes in Na concentration further indicate that the voltage dependence of polyamine block was governed by ion flux via open channels. However, responses to 1 msec applications of L-Glu revealed slow voltage-dependent rise-times, suggesting that polyamines additionally bind to closed states. A kinetic model, which included closed-channel block, reproduced these observations but required that polyamines accelerate channel closure either through an allosteric mechanism or by emptying the pore of permeant ions. Simulations with this model reveal that polyamine block confers novel activity-dependent regulation on calcium-permeable AMPA and kainate receptor responses.

Cells, Cultured↗
PubMed1996

Polyamine analogue induction of programmed cell death in human lung tumor cells.

The naturally occurring polyamines putrescine, spermidine, and spermine are required for cell growth. Based on this requirement, several polyamine analogues that interfere with polyamine function and metabolism have been synthesized as antineoplastic agents. The symmetrically substituted N1,N12-bis(ethyl)spermine (BESpm), and unsymmetrically substituted N1-ethyl-N11-[(cyclopropyl)methyl]-4, 8-diazaundecane (CPENSpm) have previously been shown to cause rapid cytotoxicity of NCI H157 cells, with concurrent high induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. However, the precise mechanism(s) of the cytotoxic action of the compounds is not known. We now demonstrate that treatment with either BESpm or CPENSpm results in morphological and biochemical changes consistent with the activation of programmed cell death pathways, and that the unsymmetrically substituted CPENSpm more rapidly activates the death program. These studies suggest that the cell type-specific cytotoxicity of these polyamine analogues may be a result of their ability to selectively activate the cell death pathway in sensitive phenotypes and indicate that the relationship between the structure of the polyamine analogues and the ability to induce programmed cell death should be investigated.

Antineoplastic Agents↗
PubMed1995

Significant induction of spermidine/spermine N1-acetyltransferase without cytotoxicity by the growth-supporting polyamine analogue 1,12-dimethylspermine.

The superinduction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) has been implicated in the cell type-specific cytotoxic activity of some polyamine analogues. We now report that one polyamine analogue, 1,12-dimethylspermine (DMSpm), produces a large induction of SSAT with no significant effects on growth in the human large cell lung carcinoma line, NCl H157. This cell line has been demonstrated to respond to other analogues with SSAT superinduction and cell death. Treatment of the lung cancer cell line with DMSpm produces a rapid increase in SSAT activity and a near complete depletion of the natural polyamines. Additionally, DMSpm supports cell growth in cells which have been depleted of their natural polyamines by the ornithine decarboxylase inhibitor, 2-difluoromethylornithine. The current results suggest that significant induction of SSAT can occur in the absence of cytotoxicity when the inducing polyamine analogue can support growth and that increased SSAT activity alone is not sufficient for cytotoxicity to occur.

Acetyltransferases↗