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Polyamines and their derivatives as modulators in growth and differentiation.

The polyamines and their derivatives are essential for life in eukaryotic and most prokaryotic cells, but their exact role in preserving cell function is not clear. These polyamines provide endogenous cations and thus participate in regulation of the intracellular pH; in addition, polyamine derivatives modulate cell growth and differentiation. The naturally occurring monoacetyl derivatives can induce increased activity of ornithine decarboxylase, the first enzyme in polyamine synthesis, and thus produce positive feedback to their production. The diacetyl derivatives of putrescine and of the synthetic analogue, 1,6-diaminohexane, induce differentiation and inhibit growth in many types of cells in vitro. In addition, they inhibit the proliferative and secretory response of normal B lymphocytes to B-cell mitogens and reduce production of antibodies in vitro. They also inhibit the proliferation of chronic lymphocytic leukemia cells (a B-lymphocyte leukemia). The parent polyamines are post-translational modifiers of proteins, and hypusine, a derivative of spermidine, is a covalently bound constituent of the eukaryotic protein synthetic initiation factor, eIF-4D. Although these various actions do not at present fall into a coherent pattern, they clearly indicate that polyamines and their derivatives play an important part in modulating cell proliferation and differentiation.

Cell Differentiation↗
PubMed1986

Blood-brain barrier breakdown by cold injury. Polyamine signals mediate acute stimulation of endocytosis, vesicular transport, and microvillus formation in rat cerebral capillaries.

Polyamines have been previously implicated in the mediation of blood-brain barrier breakdown induced by cryogenic injury (H Koenig, AD Goldstone, CY Lu, Biochem Biophys Res Commun 116:1039, 1983). We studied acute (less than 5 minute) changes in capillary ultrastructure, microvascular permeability, and the levels of polyamines and their rate regulating synthetic enzyme ornithine decarboxylase (ODC) in rat cerebral cortex after focal cold injury. Microvascular permeability was measured by relative transport of intravenously administered fluorescein. Capillary ultrastructure was studied by quantitative stereology and morphometry after intravenous administration of horseradish peroxidase. Focal cold injury induced a 2.5-, 3.8-, 1.7-, and 1.4-fold increase in the levels of ODC, putrescine, spermidine and spermine, and a 46-fold increase in fluorescein uptake in perilesional cortex. Few capillaries in control cortex contained endocytic pits or horseradish peroxidase-positive vesicles, whereas most capillaries near lesions showed these structures. Cryoinjury induced a 5-fold increase in the relative volume of microvilli and horseradish peroxidase vesicles, a 2.3-fold increase in area of luminal endocytic pits, and a 6.3-fold increase in area of abluminal exocytic pits. The ODC inhibitor alpha-difluoromethylornithine blocked the cryoinjury-induced changes in ODC, polyamines, fluorescein uptake, and capillary ultrastructure. Putrescine negated the effect of alpha-difluoromethylornithine or capillary ultrastructure, and was previously shown to nullify the alpha-difluoromethylornithine effects on polyamines and fluorescein permeability (cited above). These data link rapid changes in ODC and polyamines to blood-brain barrier breakdown, and suggest that the abnormal permeability is associated with an acute, polyamine-mediated stimulation of microvillus formation, endocytosis, and vesicular transport in capillary endothelium.

Animals↗
PubMed1988

Effect of polyamine depletion on c-myc expression in human colon carcinoma cells.

Polyamine depletion generally results in an inhibition of cell growth. However, the precise role of polyamines in the regulation of cell proliferation is unknown. In the present study, we demonstrate that polyamine depletion induced by 2-difluoromethylornithine in COLO 320 human colon carcinoma cells results in a greater than 90% decrease in expression of a key gene in the maintenance of cell growth, the c-myc protooncogene. The decrease in c-myc expression accompanying polyamine depletion appears to occur at the transcriptional level. It is not simply a result of decreased growth rate since growth-inhibited cells at confluence maintain a high level of c-myc expression. It is also due to a change in cell cycle phase distribution and is not a reflection of a generalized decrease in gene expression which accompanies a decrease in cellular proliferation. Thus, the expression of the histone H2A gene was similar to and temporally paralleled the growth status of both treated and untreated cells, while the beta-actin and ornithine decarboxylase genes actually had increased expression during polyamine depletion. These studies demonstrate that polyamines may be critical to the expression of c-myc and suggest one mechanism by which they modulate cell growth.

Actins↗
PubMed1988

Polyamine depletion and growth inhibition in Candida albicans and Candida tropicalis by alpha-difluoromethylornithine and cyclohexylamine.

The ability of two known inhibitors of polyamine synthesis, alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and cyclohexylamine, an inhibitor of spermidine synthase, to inhibit the in vitro growth and polyamine synthesis of clinical isolates of Candida tropicalis and Candida albicans was examined. Treatment of C. tropicalis and C. albicans with either DFMO or cyclohexylamine resulted in depletion of cellular polyamines and inhibition of growth. The growth inhibition produced by each of these compounds was completely reversed by exogenous polyamines. Depletion of polyamines by low concentrations of DFMO significantly enhanced the growth inhibitory activity of cyclohexylamine versus C. albicans. DFMO inhibited ODC activity in both C. albicans and C. tropicalis. These findings document the ability of cyclohexylamine and DFMO to inhibit polyamine synthesis and growth in clinically important species of Candida.

Candida↗
PubMed1988

Clinical usefulness of an enzymatic determination of total urinary polyamines, excluding cadaverine.

In one widely used enzymatic method for urinary polyamines, the total concentrations of four polyamines--putrescine, spermidine, spermine, and cadaverine--are determined. We report here a simple enzymatic method for measuring the total concentrations of urinary polyamines except cadaverine. The coefficients of variation (CV) for within-run measurements by this method were 4.3% (means = 17.2 mumol/L) and 1.5% (means = 66.5 mumol/L), between-run CVs were 4.8% (means = 16.8 mumol/L) and 1.8% (means = 67.5 mumol/L). The central 95% normal reference interval was 12.3-29.1 mumol/g creatinine for men and 14.1-36.8 mumol/g creatinine for women. In some cases, physiological variations in urinary polyamine excretion were large, mainly because of variations in cadaverine excretion, even in health. Pathological changes in polyamine production in the body may therefore be more easily shown by the excretion of total polyamines excluding cadaverine than by that including cadaverine.

Adult↗
PubMed1988

[Changes in plasma, erythrocytes and tissue polyamine levels in patients with colorectal cancer].

Polyamines (putrescine, spermidine, spermine) are closely linked to cellular synthesis of DNA, RNA and protein, and are thought to be an indicator of cell proliferation. Plasma, erythrocytes and tissue polyamine levels in 58 patients with colorectal cancer were measured to survey the relationship between polyamines and stage classification. The polyamine levels of plasma, erythrocytes and tissue in patients were increased significantly compared with those of controls. Plasma spermine and erythrocytes spermidine and spermine levels were increased with the advance of stage. In plasma and erythrocytes, spermidine/spermine ratios were decreased in accordance with the stages. On the contrary, the polyamine levels and the ratio in cancer tissue were not varied in all stages. These results present the following conclusions. Although cancer tissue has higher proliferative activity than normal mucosa, these activities of main tumors in each stage are not fluctuated. The polyamine levels in plasma and erythrocytes are possibly influenced by tumor burden and therefore those could be an useful marker for indicating the stage of colorectal cancer.

Colonic Neoplasms↗
PubMed1987

Relative abilities of bis(ethyl) derivatives of putrescine, spermidine, and spermine to regulate polyamine biosynthesis and inhibit L1210 leukemia cell growth.

It has been shown previously (Porter et al., Cancer Res., 45: 2050-2057, 1985) that the N1,N8-bis(ethyl) derivative of spermidine has significant antiproliferative activity which appears to derive from its regulatory effects on the polyamine biosynthetic pathway, particularly on ornithine decarboxylase activity. In the present study, N1,N4-bis(ethyl)putrescine (BEP) and N1,N12-bis(ethyl)spermine (BESm) were compared with N1,N8-bis(ethyl)spermidine (BES) in their ability to inhibit cell growth and regulate polyamine biosynthesis. With cultured L1210 murine leukemia cells, the IC50 values at 48 h were approximately 2 mM for BEP, 30 microM for BES, and 1 microM for BESm making the latter the most effective polyamine inhibitor or analogue thus far identified. At concentrations which approximated IC50 values and yielded similar intracellular concentrations at 48 h (1500-2000 pmol/10(6) cells), the effects of the analogues on polyamine biosynthesis generally correlated with their antiproliferative activity. BEP, at 1 mM, exerted relatively minor effects on polyamine biosynthesis. By contrast, 100 microM BES totally eliminated ornithine decarboxylase activity, depleted putrescine and spermidine pools, and decreased spermine pools by 40%. AdoMet decarboxylase activity was lowered slightly. The most impressive effects were obtained with 10 microM BESm which decreased ornithine and AdoMet decarboxylase activities by 99 and 84%, respectively; depleted putrescine and spermidine pools; and decreased spermine pools by 73%. None of the analogues, at 1 or 3 mM, had significant direct inhibitory effects on the decarboxylase activities from untreated cells with the exception of BESm which inhibited ornithine but not AdoMet decarboxylase activity. Thus, the effects of the analogues on these enzymes in treated cells are presumed to be mainly mediated by regulatory mechanisms. In this regard, BESm was superior to BES since both ornithine and AdoMet decarboxylase activities were suppressed. Given its unique activities, BESm would seem to have potential as both an antiproliferative agent and also as an experimental probe for studying regulation of the polyamine pathway, particularly AdoMet decarboxylase.

Adenosylmethionine Decarboxylase↗
PubMed1987

[Polyamine levels and biosynthesis in leukocytes during leukemic transformation].

The content of polyamines, rate of their biosynthesis, and activity of ornithine decarboxylase (ODK), the key regulatory enzyme in the polyamine biosynthetic pathway, have been studied in the leukocytes of healthy persons and of patients with various forms of leukemia. The polyamine levels and the rate of their biosynthesis were considerably higher in lymphocytes than in granulocytes. In leukemias, as the cell population rejuvenated, both the polyamine content and the spermidine/spermine ratio were found to be markedly elevated approaching the maximal values in human blast cells of K-562 line. The leukemic transformation of myeloid cells was associated with the increase in the ornithine decarboxylase activity and in the rate of polyamine synthesis, whereas these items were significantly lowered in lymphoid leukemic cells. The changes observed in polyamine metabolism in leukemias are considered to be related to the proliferative and biosynthetic activity of the cells.

Humans↗
PubMed1985

Effect of inhibition of polyamine biosynthesis by DL-alpha-difluoromethylornithine on the growth and melanogenesis of B16 melanoma in vitro and in vivo.

The objective of the present study was to investigate the effect of polyamine depletion by alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, on the growth and differentiation of B16 melanoma cells grown in culture and also as solid tumors in mice. Polyamine depletion by DFMO (2.5 mM) resulted in a complete inhibition of cell growth in culture and a 90% inhibition of viability of melanoma cells as determined by clonogenic assay at the end of 7 days after DFMO treatment. These results indicate that polyamine depletion induced by DFMO is cytotoxic to B16 melanoma cells in culture. Furthermore a 2- to 5-fold increase in tyrosinase activity and 10-fold accumulation of melanine were observed in polyamine depleted cells compared to control cultures. These effects of DFMO could easily be reversed by the addition of putrescine simultaneously with DFMO. Administration of different doses of DFMO in drinking water to B16 melanoma tumor bearing mice also resulted in an increase in tyrosinase activity and a dose dependent inhibition (86-90%) of tumor growth. Although one cannot rule out the possibility of induction of differentiated phenotype as a result of antiproliferative activity of DFMO, the data presented indicate that the unique sensitivity of melanoma to DFMO may be due to a combination of cell growth inhibition and concomitant induction of differentiation upon polyamine depletion. The results of the present study indicate that polyamines play an important role in growth and differentiation of melanoma and also provide an example of inhibition of tumor cell growth by induction of cellular differentiation.

Animals↗
PubMed1979

[Concentrations of polyamines in maternal and umbilical-cord blood and in the amniotic fluid during normal human pregnancy and in feto-placental insufficiency].

Blood maternal polyamines during normal pregnancy exhibit an important augmentation around the 10th and the 34th-38th week, and a minor increase between the 20th-25th week of pregnancy. These peaks coincide with extremely important metabolic events in the feto-placental unit such as maximal growth rate in the placenta and fetus, respectively. The levels of polyamines measured from the 38th to 41th week in the blood of the umbilical cord are higher than in the blood of the mother. Putrescine, spermidine and spermine are not detectable when measured in the non-hydrolized amniotic fluid during normal pregnancy, instead a band with a lower Rf than spermine is present. In case of feto-placental insufficiency polyamine concentration in maternal blood are well below the normal values, from the 34th to 38th week of pregnancy. Such a behaviour appears for umbilical cord blood at the 38th and 39th week. Also the unknown polyamine of the amniotic fluid undergoes evident modification in feto-placental insufficiency. These results show that blood polyamines of the mother are probably of fetal origin, and that modified pattern of maternal polyamines may indicate an insufficient body growth of the fetus.

Adult↗
PubMed1979

[Serial evaluation of blood polyamines in children treated with growth hormone].

Blood polyamines were evaluated in normal children of various ages (from infancy to adolescence). Polyamines show a distinctive pattern: maximal values were observed during infancy; they decrease during childhood and again increase at puberty. After i.m. injection of Human Growth Hormone (HGH), polyamine concentrations increase significantly in the first 60 minutes. Polyamines increase more in patients previously untreated or treated intermittently with HGH than in patients under continuous treatment. The results suggest that in humans as well as in animals, polyamines could be involved in the growth processes and that the effect of HGH probably consists in a stimulation of polyamine synthesis.

Adolescent↗
PubMed1983

Epidermal keratinocytes actively maintain their intracellular polyamine levels.

Increased cellular polyamine levels are thought to be essential for epidermal keratinocyte proliferation. However, a number of studies report that the induction of keratinocyte proliferation and of ornithine decarboxylase, the rate-limiting enzyme of putrescine, spermidine and spermine biosynthesis, is not concordantly expressed. The relationship between epidermal keratinocyte polyamine synthesis and proliferation was studied in neonatal mouse keratinocyte cultures using specific inhibitors of ODC activity to decrease the intracellular polyamine levels. The ODC inhibitors alpha-methyl ornithine (alpha-Me-Orn), alpha-hydrazino ornithine (alpha-HO) and difluoro-alpha-methylornithine (alpha-DFMO) did not significantly inhibit epidermal keratinocyte proliferation at 5 X 10(-3) to 10(-4) M concentrations. At these doses, only alpha-DFMO was seen to decrease (by 70%) the cellular levels of putrescine, but not of spermidine or spermine. Epidermal keratinocyte growth in the higher dose of 20 mM alpha-DFMO, however, did not decrease the cellular levels of putrescine. Polyamine analyses of the spent medium showed that growth in 10 mM alpha-DFMO decreased the normal epidermal cell transport of putrescine and spermidine into the medium. At 20 mM alpha-DFMO concentration, the keratinocytes actually transported, intracellularly, the putrescine and spermidine that are naturally found in the foetal bovine component of the growth medium. We conclude from these studies that epidermal keratinocyte polyamine levels are determined by both the rate of synthesis, and of the transport of these amines into the extracellular medium. Since epidermal keratinocytes actively maintain specific polyamine levels, it appears that these molecules are essential for epidermal keratinocyte function.

Animals↗
PubMed1983

Arginase activity and polyamine biosynthesis in psoriasis.

Polyamine biosynthesis and arginase activity in psoriasis were studied using keratotome strips and suction blister roofs as specimens. In the uninvolved psoriatic skin a slight (1.3-fold; p less than 0.05) increase in the spermidine level was observed compared with control skin. There was also a 1.2-fold increase (p less than 0.05) in the spermidine/spermine molar ratio, which is considered to be an indicator of proliferation activity. No changes were noted in other polyamines or polyamine-synthesizing enzymes ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AMDC) in the uninvolved psoriatic skin vs. control skin. Neither was there any significant difference in the arginase activity. In psoriatic lesions the levels of all polyamines, as well as the activities of biosynthetic enzymes, were significantly (p less than 0.001) elevated. The putrescine level was elevated to 2.5-fold, spermidine to 2.7-fold and spermine to 1.4-fold. The enzyme activities expressed severalfold increases. The enhancement of arginase activity was less prominent than that of polyamine-synthesizing enzymes, but the increase from 271 +/- 88 to 354 +/- 126 mumol/g/h (1.3-fold) was statistically significant (p less than 0.001; paired t-test). The increase in arginase activity in suction blister roofs, which represents pure epidermis, was more pronounced than that in keratotome strips, i.e. about double. The results show thus that polyamine biosynthesis is significantly enhanced in psoriatic lesions, but there is only a slight difference between the uninvolved psoriatic skin and control skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

[Various aspects of the biological role of polyamines in normal and malignant growth].

The data on location of polyamines (spermine, spermidine, putrescine) in cells of different tissues and organs, intracellular polyamines distribution and the factors controlling polyamine metabolism are reviewed. Certain aspects of a regulatory role of polyamines in nucleic acid and protein synthesis and of changes in the activity of the enzymes participating in the synthesis and degradation of polyamines in the neoplastic growth are dealth with. The data available in literature and the results of the authors own investigations concerning the use of the polyamine test for diagnosis and evaluation of malignant tumours treatment efficiency are presented.

Acetylation↗
PubMed1984

Physiological effects in bovine lymphocytes of inhibiting polyamine synthesis with ethylglyoxal bis(guanylhydrazone).

Previous results have suggested that ethylglyoxal bis(guanylhydrazone) is a more specific inhibitor of polyamine biosynthesis than the widely used methylglyoxal bis(guanylhydrazone). The physiological effects on mitogenically activated lymphocytes of polyamine depletion with ethylglyoxal bis(guanylhydrazone) were examined. In the presence of ethylglyoxal bis(guanylhydrazone) and the ornithine decarboxylase inhibitor alpha-difluoromethylornithine, the cellular contents of putrescine, spermidine, and spermine were decreased by 75 to 90, 65 to 80, and 40 to 60%, respectively, compared with control cultures. Inhibition of DNA synthesis in these polyamine-deficient cells was always greater than that of protein synthesis. Upon addition of spermidine to the deficient cells, the cellular spermidine content was restored within 4 hr, but the complete recovery of macromolecular synthesis took 10 to 20 hr. Thymidine kinase and DNA polymerase alpha activities in polyamine-deficient cells were lower than those in normal cells, whereas RNA polymerase II and leucyl transfer RNA synthase activities were nearly equal to those in normal cells. These results and studies with 2-dimensional gel electrophoresis raise the possibility that polyamines may regulate the synthesis of specific proteins. Decreased synthesis of replication proteins in polyamine-deficient cells may be one reason for the reduced synthesis of DNA.

Animals↗
PubMed1983

Inhibition of cells in culture by polyamines does not depend on the presence of ruminant serum.

Using T-lymphocyte (T-LC) and granulocyte colony (GC) assays with truly proliferating cells, the inhibitory dose-response relationships of spermine and spermidine in the presence of selected sera have been examined. In contrast to previous studies which used [3H]thymidine uptake as an index of proliferation, in vitro inhibition by polyamines was shown to require neither foetal calf serum (FCS) nor the addition of any exogenous polyamine oxidase. Cells grown in the absence of FCS were between 5-50% as sensitive to polyamines as in its presence. By using specific inhibitors of polyamine oxidase, it was shown that polyamine-elicited mitotic inhibition in the absence of FCS was still dependent on a polyamine oxidase, and evidence is presented to show that the source of the enzyme is the cells themselves.

Animals↗
PubMed1984

Characterization of the polyamine transport system in mouse neuroblastoma cells. Effects of sodium and system A amino acids.

The biochemical properties of polyamine transport system have been studied in detail in NB-15 mouse neuroblastoma cells in culture by measuring the uptake of [14C]putrescine under various experimentally imposed pharmacological conditions. Putrescine uptake in the NB-15 mouse neuroblastoma cells appeared to be a sodium-dependent process. Iso-osmotic displacement of Na+ in the assay medium with either choline or Li+ resulted in a linear decrease of putrescine uptake. Gramicidin, a channel-former ionophore, inhibited putrescine uptake by more than 90% at 20 nM. N-Ethylmaleimide at 5 mM or p-chloromercuribenzene sulfonate at 50 microM completely abolished putrescine uptake. Conversely, oxidized glutathione at 10 mM or 5,5'-dithiobis-(2-nitrobenzoic acid) at 5 microM gave a 1.3-1.4-fold stimulation after a 1-h incubation. This polyamine transport system appeared to be subjected to adaptive regulation. Polyamine antimetabolites such as alpha-difluoromethyl ornithine stimulated putrescine uptake whereas preloading of cells with polyamines inhibited putrescine uptake. Preloading cells with neutral amino acids that belong to sodium-dependent transport System A stimulated putrescine uptake by more than 8-10-fold. These results suggested that the polyamine transport system in NB-15 mouse neuroblastoma cells was sodium dependent and shared some characteristics common to other known sodium-dependent transport systems. These characteristics included (a) sensitivity to ionophores, (b) sensitivity to sulfhydryl reagents, and (c) sensitivity to intracellular contents of substrate molecules. Our data also indicated that polyamine transport may be regulated by transport System A amino acids.

Amino Acids↗
PubMed1983

A new simple enzymatic assay method for urinary polyamines in humans.

We developed a new simple enzymatic assay method for measuring urinary polyamines (total amount of putrescine, spermidine, and cadaverine), using an acylpolyamine amidohydrolase and a putrescine oxidase. First conjugated polyamines (putrescine, spermidine, and cadaverine) in urine were hydrolyzed by incubation with an acylpolyamine amidohydrolase at 30 degrees for 1 hr. then, free polyamines were separated by cation-exchange chromatography and incubated with a putrescine oxidase at 30 degrees for 30 min. Hydrogen peroxide formed in this reaction was measured spectrophotometrically (at 514 nm). Polyamine levels in urine were determined in 70 normal subjects, 124 patients with cancer, and 52 patients with diseases other than cancer. Elevation above 3 S.D.s of the normal mean was found in 90 (72.6%) of the 124 patients with cancer and in 6 (11.5%) of the 52 patients with diseases other than cancer. Serial studies in 19 patients with cancer indicated that polyamines in urine were reduced after successful surgery. Our new method is simple and rapid and therefore very useful for routine clinical application. Moreover, our data indicate that the determination of polyamine levels is useful as a marker of disease activity in patients with cancer.

Amidohydrolases↗