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PubMed1996

Isolation of a polyamine transport deficient cell line from the human non-small cell lung carcinoma line NCI H157.

In an effort to study the mechanism underlying the observed phenotype-specific response of human lung cancer cell lines to a polyamine analogue, N1,N12-bis(ethyl)spermine(BESpm), we have isolated a BESpm resistant cell line from the BESpm-sensitive large cell lung carcinoma line NCI H157. The mutant line exhibits identical growth rates in the presence or absence of the analogue. However, the overall growth of mutant cells reaches stationary phase earlier than that of the parental cells. In contrast to the parental cells, where a superinduction of spermidine/spermine N1-acetyltransferase (SSAT) is associated with BESpm toxicity, treatment of this resistant line with BESpm did not induce SSAT mRNA or enzyme activity. BESpm treatment was not effective in depleting the intracellular polyamine pools and very low intracellular BESpm levels were detected. This BESpm resistance is not mediated by multidrug resistance (MDR) protein, since these cells maintain their sensitivity to the antineoplastic agent adriamycin. Treatment of these cells with methylglyoxal bis(guanylhydrazone) (MGBG), an AdoMetDC inhibitor which enters cell using polyamine transport system, shows no inhibition of cell growth. Our data suggest that these mutant cells are deficient in polyamine transport. Consistent with this hypothesis, exogenous polyamines did not prevent difluoromethylornithine (DFMO) induced growth inhibition in the mutant cells.

Acetyltransferases↗
PubMed1998

Inhibition of cell growth in CaCO2 cells by the polyamine analogue N1,N12-bis(ethyl)spermine is preceded by a reduction in MYC oncoprotein levels.

The polyamine analogue N1,N12bis(ethyl)spermine (BESpm) is a potent inhibitor of cell proliferation and is representative of a class of agents currently in clinical trials. Previous studies have demonstrated that BESpm treatment can produce a decrease in the mRNA levels of the protooncogene c-myc resulting from decreased transcription. Investigation into the mechanism of the antiproliferative effect of BESpm in the colon cancer cell line CaCO2 indicated that significant reduction in MYC protein, but not c-myc mRNA levels, preceded cytostasis. Specificity of the downregulation of MYC expression by BESpm treatment was demonstrated by comparison to effects on the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) and the polyamine biosynthetic enzyme ornithine decarboxylase (ODC). SSAT activity rapidly increased while levels of ODC activity decreased after BESpm treatment. Measurement of intracellular polyamines demonstrated significant uptake of the analogue after 24 hours, which was concurrent with a reduction of spermine and spermidine levels. Thus, cellular uptake of BESpm mediated a reduction of polyamine levels that was associated with a decrease of MYC protein at the post-transcriptional level.

Antineoplastic Agents↗
PubMed1998

A 1H/13C inverse 2D method for the analysis of the polyamines putrescine, spermidine and spermine in cell extracts and biofluids.

The polyamines putrescine, spermidine and spermine are involved in the regulation of various metabolic processes. It is therefore desirable to detect and quantify the polyamines with NMR. We present the proton and carbon assignments for all polyamine signals obtained from PCA extracts of F98 glioma cells with high resolution using a semi-selective HSQC 2D-experiment. The biosynthesis of the polyamines in cell culture was examined using the labeled substrates [U-13C]glucose and [U-13C]glutamate. In such studies the high resolution of the semi-selective HSQC experiment at very high magnetic fields (14-19 T) allows the analysis of carbon-carbon couplings, and isotopomer patterns. The different effects of osmotic stress on the concentrations of polyamines and amino acids are also reported.

Animals↗
PubMed2000

Antitumor activity of the polyamine analog N(1), N(11)-diethylnorspermine against human prostate carcinoma cells.

BACKGROUND: Recent studies indicate that N-terminally bis-ethylated-polyamine analogs have significant antitumor activity in several human solid-tumor models. In this study, the in vitro and in vivo antitumor potential of the polyamine analog N(1), N(11)-diethylnorspermine (DENSpm) in human prostate carcinoma cells was examined. METHODS: The antiproliferative and biochemical effects of DENSpm were tested in four human prostate cancer cell lines, i.e., PC-3, TSU-pr1, DU-145, and JCA-1. The in vivo antitumor potential was explored in two groups of nude mice bearing small or more developed xenografts of the DU-145 cell line. The mice were treated with 40 mg/kg DENSpm, three times per day for two cycles of 6 days, on days 1-6 and 8-13. RESULTS: In vitro studies showed that all four tested human prostate carcinoma cell lines were sensitive to DENSpm in micromolar concentrations. In tumor-bearing mice, DENSpm clearly prevented tumor growth in both size groups, which became significant after day 17. Treatment with DENSpm evoked intracellular accumulation of the analog and various regulatory responses, e.g., downregulation of the polyamine biosynthesis, the induction of the catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), and the depletion or decrease of natural polyamines. The cellular sensitivity to growth inhibition by DENSpm only correlated with the degree of ODC inhibition and SSAT induction. CONCLUSIONS: DENSpm has sustained inhibitory effects on the growth of human prostate carcinoma cells in vitro as well in vivo. This polyamine analog may provide a new tool in the chemotherapy of prostate cancers with various phenotypes.

Acetyltransferases↗
PubMed1976

Polyamines in malignant melanoma. Urinary excretion and disease progress.

Urinary polyamine concentrations in 91 samples were assayed in 79 patients with malignant melanoma who were classified as to clinical stage, as well as to activity of disease. Patients with active disease had higher mean polyamine values, increased frequency of polyamine elevations, and increased frequency of two or more elevations, than did patients with stable disease. Elevations of a single polyamine were seen as frequently in patients whose disease was considered stable as in those who showed progression. The polyamines may be useful as guides to activity of the disease, provided further studies can identify additional sources of nonspecific elevations.

Female↗
PubMed1984

Polyamines in breast cancer.

Polyamine levels (putrescine, spermidine and spermine) in breast cancers (n = 54) were measured as a potential guide to prognosis. Values (expressed as nmol per 100 mg tumour) ranged from: 0.9 to 4.5 for putrescine, 4.2 to 29.8 for spermidine and 5.6 to 39.7 for spermine concentration. Increased intracellular polyamine levels were positively correlated with factors known adversely to affect survival after mastectomy, namely histological grade III and oestrogen-receptor negative status. Advanced T4 tumours and medullary-type carcinomas also contained high polyamine levels. Tumour size and node status did not affect polyamine levels in primary tumours. Tumours that recurred within 2 years of mastectomy had significantly higher levels of spermidine and spermine than those that did not. Breast cancer polyamine levels are a biological marker of tumour aggressiveness and can be used as a prognostic indicator of early tumour recurrence that is independent of node status.

Adult↗
PubMed1988

Calmodulin antagonist trifluoperazine inhibits polyamine biosynthesis and liver regeneration.

Polyamines are essential for cell growth and differentiation. Trifluoperazine (TFP) is a potent, competitive inhibitor of the calcium-calmodulin complex. TFP, when given to rats after partial hepatectomy, causes a significant decrease in DNA synthesis. The purpose of this study was to examine the effects of TFP on polyamine biosynthesis and on liver regeneration after partial hepatectomy. TFP (60 mg/kg, bodyweight) or saline control was administered to 80 male Sprague-Dawley rats 2 h before, 2 h after, or at the time of hepatectomy. Polyamines (putrescine, spermidine and spermine) were measured at the time of hepatectomy, and at 6, 24, 48, and 72 h after hepatectomy. TFP, when it was administered either 2 h before or at time of hepatectomy, blocked increases in putrescine that are seen normally at 6 h after hepatectomy. When TFP was given at the time of partial hepatectomy, putrescine was increased at 24 h, and then returned to normal levels at 72 h. Spermidine was inhibited at 24 h, but not at 48 and 72 h. Spermine was not significantly altered at any time. The administration of TFP 2 h after hepatectomy did not significantly alter concentrations of polyamines. The weight of regenerating liver was decreased by TFP at 48 h (23 per cent) and 72 h (22 per cent) after hepatectomy. These findings provide evidence that the calcium-calmodulin complex is required for the synthesis of liver polyamines before liver regeneration can proceed.

Animals↗
PubMed2003

Direct tris(2,2'-bipyridyl)ruthenium (II) electrochemiluminescence detection of polyamines separated by capillary electrophoresis.

Capillary electrophoresis (CE) with tris(2,2'-bipyridyl) ruthenium (II) (Ru(bpy)3(2+)) electrochemiluminescence (ECL) detection technique was developed for the analysis of four polyamines (putrescine (Put), cadaverine (Cad), spermidine (Spd), and spermine (Spm)) analysis. The four polyamines contain different amine groups, which have different ECL activity. There are several parameters which influence the resolution and ECL peak intensities, including the buffer pH and concentrations, separation voltage, sample injection, electrode materials, and Ru(bpy)3(2+) concentrations. Polyamines are separated by capillary zone electrophoresis in an uncoated fused-silica capillary (50 cmx25 micro m (ID) filled with acidic phosphate buffer (200 mmol/L phosphate, pH 2.0) - 1mol/L phosphoric acid (9:1 v/v) and a separation voltage of 5 kV (25 micro A), with end-column Ru(bpy)3(2+) ECL detection. A 5 mmol/L Ru(bpy)3(2+) solution plus 200 mmol/L phosphate buffer (pH 11.0) is added into the reagent reservoir. The calibration curve is linear over a concentration range of two or three orders of magnitude for the polyamines. The analysis time is less than 25 min. Detection limits for Put and Cad are 1.9x10(-7) mol/L and 7.6x10(-9) mol/L for Spd and Spm, respectively. Intraday and interday relative standard deviations of ECL peak intensities are less than 8%. The main advantages of this CE-ECL detection technique for polyamines analysis presented herein are the omission of chemical derivatization of the analytes and the high selectivity.

2,2'-Dipyridyl↗
PubMed1980

Elevation of serum polyamines in malignant lymphomas and acute myeloid leukemia.

In a study of 89 cases of hematological cancers including 55 cases of Hodgkin's disease, 21 of non-Hodgkin lymphoma and 13 of acute myeloid leukemia, the serum total polyamines were considerably elevated (1.2-5.7 nmol/ml) as compared to observations on control values for eight healthy individuals (0.62-0.87 nmol/ml). The assay procedure was based on enzymes oxidizing polyamines isolated from Russell's viper venom. Serial determination of polyamines in the sera of eight cases of Hodgkin's disease done before and after chemotherapy or radiotherapy showed positive correlation with clinical status of the disease. Analysis of individual polyamines in four patients with Hodgkin's disease indicated that putrescine may be a more sensitive marker of the diseased state. By the present method it was undetected in the control sera but rose significantly in the sera of patients with Hodgkin's disease. Overall data suggest that serum polyamines may be useful as indicators of onset of relapse in patients with Hodgkin's disease and could thus be helpful in early start of treatment.

Adult↗
PubMed1984

Red blood cell polyamines in mice bearing the Lewis lung carcinoma (3LL) and in patients with bronchopulmonary cancers.

Experimentally, during Lewis lung carcinoma (3LL) growth, the red blood cell (RBC) polyamine levels increase with tumor volume and are inversely correlated to tumoral concentrations of spermidine and spermine. The RBC level of spermidine is continually correlated to both the volume and the tumoral concentration of this polyamine. Clinically, high levels of RBC polyamine are observed in cases of squamous-cell carcinoma or anaplastic cancer, and not in cases of adenocarcinoma. RBC polyamine levels only permit the establishment of statistical differences between groups of patients. Therefore, clinical use of these molecules as tumor markers depends on an understanding of polyamine distribution within blood.

Adenocarcinoma↗
PubMed1991

Differential sensitivity of various human tumors to inhibition of polyamine biosynthesis in vivo.

Polyamines are essential for normal and neoplastic growth. Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the polyamine biosynthetic pathway. alpha-Difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor of ODC, and a known anti-neoplastic agent. The purpose of this study was to examine the susceptibility of various human cancers to inhibition by DFMO in vivo. We have studied three human pancreatic adenocarcinomas, designated CAV, SKI, and PGER, two human colon adenocarcinomas (LS-180 and WIDR), and three metastatic cell lines of a human gastric adenocarcinoma (BHM, BMM, BLM) that were growing in congenitally athymic (nude) Balb/c mice. Mice bearing each tumor were divided into two groups; one group served as controls and the other group received DFMO 3% in drinking water. Tumor growth and weight, and content of DNA, RNA, protein and polyamines were determined and correlated. DFMO significantly inhibited the growth of three of the three gastric tumors, two of the three pancreatic tumors and neither of the two colon tumors. The tumor content of DNA, RNA and protein exhibited a pattern that was parallel to tumor growth. The tumor polyamine concentration did not correlate with sensitivity to DFMO. These findings provide clear evidence for important differences in the sensitivity of various human cancers to growth inhibition by DFMO and indicate that endogenous polyamine levels alone do not predict the sensitivity of the tumors to DFMO.

Adenocarcinoma↗
PubMed1991

Killer polyamines?

Mammalian cells can rapidly make large changes in their rate of polyamine biosynthesis in response to mitogenic and trophic signals. However, cultured cells seem to grow adequately as long as they are supplied a steady but unregulated supply of polyamines. This implies that complex and rapid changes in polyamine synthesis serve a function in a special rather than a general biological context. We suggest that the appropriate context in which regulation of polyamines mediates crucial functions is the mammalian embryo and that one function of polyamines is to act as substrate in an oxidative pathway that arbitrates programmed cell death.

Animals↗
PubMed1991

A new perspective on ornithine decarboxylase regulation: prevention of polyamine toxicity is the overriding theme.

The polyamines are essential cellular components for growth. Control of a key regulated enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), as a function of growth, is an area of intense interest. A unique regulatory property of ODC is the short half-life of the protein, which has been suggested to be an important factor in rapid activation of polyamine biosynthesis after cells are mitogenically stimulated. In this paper, it is argued that the biological significance of the short half-life of ODC is unrelated to the rate of its induction to a new steady state by growth factors, which is in fact limited by the relatively long half-life of the ODC mRNA. Instead, I suggest that the rapid turnover of ODC protein becomes of significance when cells cease growth and expeditious downregulation of the enzyme is important in preventing polyamine overproduction, which would result in cytotoxicity in the arrested cells. Although mitogenic activation of ODC expression has been studied extensively, there is very little known about the mechanisms controlling downregulation of polyamine biosynthesis during the arrest of animal cell growth. These considerations suggest that this would be a fertile area of future inquiry.

Animals↗
PubMed1988

Characterization of a polyamine transport system in murine embryonic palate mesenchymal cells.

Polyamines (putrescine, spermidine, and spermine) are normal cellular constituents able to modulate cellular proliferation and differentiation in a number of developing systems. Ornithine decarboxylase (ODC), the rate-limiting enzyme in the polyamine biosynthetic pathway, has been shown to be causally related to an increase in glycosaminoglycan synthesis in murine embryonic palatal mesenchyme cells (MEPM). In order to understand other mechanisms that exist to regulate polyamine levels in cells derived from the developing craniofacial area, the present study investigated the capacity of MEPM cells to accumulate exogenous putrescine and tests the hypothesis that polyamine transport can serve as an adaptational response of MEPM cells to a change in their ability to synthesize polyamines. Transport was initiated in confluent cultures of MEPM cells by the addition of 0.1 microCi/ml of 14C-putrescine. The rate of transport, monitored for 20-120 minutes, was found to be a time-dependent saturable process. The rate of initial transport, determined by incubating MEPM cells for 15 minutes in the presence of different concentrations (1.0-20.0 microM) of 14C-putrescine, was also found to be saturable, suggesting a carrier-mediated event. Lineweaver-Burk analysis of these data revealed an apparent Km of 5.78 microM and a Vmax of 2.63 nmol/mg protein/15 minutes. Transport measured either at 4 degrees C or in the presence of 2-4 DNP was dramatically inhibited. Thus, putrescine transport is an active process, dependent upon metabolic energy. Conditions in which 1) NaCl was iso-osmotically replaced with choline chloride or 2) the Na+-electrochemical gradient was dissipated with Na+, K+-specific ionophores resulted in a decreased rate of transport indicating that putrescine transport in these cells is Na+ dependent. Noncompetitive inhibition assays utilizing sulfhydryl reagents that blocked sulfhydryl groups inhibited putrescine transport, suggesting that sulfhydryl groups are important for putrescine uptake. Competitive inhibition assays demonstrated that while spermidine and spermine inhibited putrescine uptake, ornithine did not inhibit transport. Spermidine, spermine, and putrescine thus appear to share a common transport system that is separate from that for ornithine. Putrescine transport is subject to adaptive regulation in both exponentially growing and confluent cultures of MEPM cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The level of substrate ornithine can alter polyamine-dependent DNA synthesis following phorbolester stimulation of cultured hepatoma cells.

Although the precise intracellular function(s) of the polyamines remain incompletely defined, a myraid of evidence now shows that the polyamines must accumulate or be maintained at a specific intracellular concentration in order for all mammalian cells to grow or divide. The initial step in polyamine biosynthesis normally involves the decarboxylation of ornithine by the enzyme ornithine decarboxylase (ODCase E.C. 4.1.1.17) to yield putrescine. Increases in the steady-state level of intracellular ornithine have been reported to markedly alter the accumulation of the polyamines following stimulation of Reuber H35 Hepatoma cells with 12-O-tetradecanoylphorbol-beta-acetate (TPA) in the presence of serum (Wu and Byus: (Biochem. Biophys. Acta 804:89-99, 1984); Wu et al.: (Cancer Res. 41:3384-3391, 1981). We wished to determine whether or not incubation of H35 hepatoma cells with exogenous ornithine would result in a stimulation of DNA synthesis following treatment with the mitogens TPA and insulin. For these studies, H35 cells were maintained under serum-free conditions for 2-3 days in order to obtain synchronous cultures suitable for analysis of the level of DNA synthesis. Cultures treated in this manner were highly viable, maintained similar growth rates, and possessed the equivalent levels of intracellular ornithine and polyamines as the serum-containing cultures. Arginine levels, however, were approximately twofold higher following culture under serum-restricted conditions for 3 days. The addition of exogenous ornithine (0.5 mM) was accompanied by a 4-5-fold increase in intracellular steady-state ornithine levels and by a 6-8-fold increase in the presence of TPA and ornithine. In a manner identical to the serum-containing cultures (Wu and Byus (1984] the addition of TPA and exogenous ornithine to the serum-free cells caused a dose-dependent increase in intracellular putrescine (up to 5-fold) and a concomitant decrease in ODC activity in comparison to stimulation with TPA alone. The addition of TPA led to a 3-5-fold increase in the incorporation of tritiated thymidine into DNA. In the presence of exogenous ornithine, TPA-induced DNA synthesis was further stimulated more than twofold in a dose-dependent manner. Insulin (10(-10)-10(-8) M) proved to be more efficacious as a mitogen in the H35 cells and led to greater stimulation of DNA synthesis than TPA. Insulin alone also resulted in a higher steady-state level of ornithine and putrescine in comparison with TPA alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Polyamine regulation of Na+/glucose symporter expression in LLC-PK1 cells.

Addition of polyamines or their analogs to newly confluent LLC-PK1 cells resulted in down-regulation of Na(+)-dependent glucose transport (symport) activity. Polyamines prevented the induction of this symporter by the differentiation inducer hexamethylene bisacetamide (HMBA) but did not influence induction by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Partial depletion of endogenous polyamines after addition of alpha-difluoromethylornithine (DFMO) resulted in a 4 to 5-fold increase in symporter expression. Symporter induction by either HMBA or DFMO was inhibited by the protein kinase inhibitor H-7 but H-7 did not affect symporter induction by IBMX. Changes in symporter activity were accompanied by changes in levels of the 75 kD symporter subunit detected by Western blot. Cultures exposed to HMBA exhibited reduced levels of ornithine decarboxylase activity. Our results suggest that induction of symporter expression by HMBA may be mediated in part by its effects on polyamine metabolism, and point to parallel roles of polyamines and cyclic AMP in regulating the expression of this physiologically important renal transport system.

Acetamides↗
PubMed2006

Polyamine depletion by ODC-AdoMetDC antisense adenovirus impairs human colorectal cancer growth and invasion in vitro and in vivo.

BACKGROUND: Polyamine biosynthesis is controlled primarily by ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC). Polyamine concentrations are elevated in colorectal cancer. Depletion of polyamine content in colorectal cancer by chemotherapy is related to tumor regression and impaired tumorigenicity. The current study evaluates the therapeutic effects of antisense ODC and AdoMetDC sequences on colorectal cancer in vitro and in vivo. METHODS: Antisense ODC and AdoMetDC sequences were cloned into an adenoviral vector (Ad-ODC-AdoMetDCas). The human colon cancer cell lines, HT-29 and Caco-2, were infected with Ad-ODC-AdoMetDCas as well as with control vector. Viable cell counting, determination of polyamine concentrations, cell cycle analysis, and Matrigel invasion assays were performed in order to assess properties of tumor growth and invasiveness. Furthermore, the antitumor effects of Ad-ODC-AdoMetDCas were also evaluated in vivo in a nude mouse tumor model. RESULTS: Our study demonstrated that adenovirus-mediated ODC and AdoMetDC antisense expression inhibits tumor cell growth through a blockade of the polyamine synthesis pathway. This inhibitory effect cannot be reversed by the administration of putrescine. Tumor cells were arrested at the G1 phase of the cell cycle after gene transfer and had reduced invasiveness. The adenovirus also induced tumor regression in established tumors in nude mice. CONCLUSIONS: Our study suggests that Ad-ODC-AdoMetDCas has antitumor activity and therapeutic potential for the treatment of colorectal cancer.

Adenosylmethionine Decarboxylase↗
PubMed2006

Interaction of polyamine gene vectors with RNA leads to the dissociation of plasmid DNA-carrier complexes.

BACKGROUND: Plasmid DNA (pDNA) dissociation from polyamine gene vectors after cellular uptake has not been well characterized. A more detailed understanding of this process could lead to more efficient gene transfer agents. Since RNA is present in the cytoplasm at high concentrations and due to its structural similarity to DNA, we were interested in its conceivable interaction with polyamine gene vectors. METHODS: In a first set of experiments gene vectors were incubated in cell lysate and pDNA release was investigated by Southern blot analysis with or without RNase A pretreatment and by confocal laser scanning microscopy. Further, interaction of polyamine gene vectors with RNA was investigated by fluorescence quenching assay. These methods were complemented by a functionality assay using isolated nuclei. RESULTS: The incubation of gene vectors with cell lysate resulted in the dissociation of pDNA from the complexes. This effect was abolished when the cell lysate was pretreated with RNase A. The addition of RNA in the absence of cell lysate led also to a dissociation of pDNA. This process commenced instantaneously after the addition of RNA as analyzed by fluorescence quenching. When gene vectors were incubated in cell lysate containing isolated nuclei, the dissociation of pDNA from the polyamine gene vectors occurred preferentially extranuclearally as confirmed by confocal laser scanning microscopy. These results were further corroborated in a functional assay. CONCLUSIONS: These data suggest that RNA induces pDNA dissociation from the polyamine gene vectors. Furthermore, this process apparently occurs in the cytoplasm before the gene vectors enter the nucleus.

Cell Nucleus↗