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At least 145 records · Page 8Linked to original sources
PubMed1989

Mononuclear cell polyamine content associated with myeloid maturation in patients with leukemia during administration of polyamine inhibitors.

Fourteen patients with acute leukemia in relapse were treated with difluoromethylornithine (DFMO) alone or in combination with methylglyoxal-bis(guanylhydrazone) (MGBG) as part of Phase I studies. Five patients included in the trial exhibited morphologic evidence of cellular differentiation during the course of treatment. In one patient who exhibited no blasts and a normal white blood cell differential at the end of treatment the mononuclear cell content of all three polyamines declined after an initial increase in spermidine and spermine content. In the other patients in whom the cellular maturation was less pronounced the mononuclear cell polyamine levels remained stable or increased over the treatment time. No absolute difference was apparent between the cellular polyamine levels detected in patients at the times of the greatest increase in per cent circulating neutrophils as compared to the cellular levels present in patients whose circulating mononuclear cell number were increasing. Circulating mononuclear cell putrescine, spermidine, and spermine levels varied over two orders of magnitude from patient to patient and the range of values detected in each state completely overlapped those present in the other. It does not appear from the present study that there is a consistent human leukemic cell polyamine content at which cellular differentiation occurs.

Adolescent↗
PubMed1984

Polyamines in human brain tumors. A correlative study between tumor, cerebrospinal fluid and red blood cell free polyamine levels.

Polyamine levels have been studied in brain tumor patients. We focused our study on the relationship between tumor, cerebrospinal fluid (CSF) and red blood cell (RBC) polyamine levels. Our results are the following: Polyamine levels in CSF are consistently increased, whatever the histological type may be. The highest tumoral concentrations are found in medulloblastoma. In glioblastomas, the RBC spermidine levels are higher than in the other types of tumors and there is a highly significant correlation between the spermidine/spermine ratio in tumor and RBC. Therefore, RBC polyamine determination might be of clinical interest in the monitoring of patients with glioblastomas.

Astrocytoma↗
PubMed1992

A novel anticancer treatment for xenoplanted human gastric cancer using polyamine antimetabolites in a low polyamine diet.

The aim of the present study was to evaluate a new anticancer treatment for gastrointestinal cancer, using a combination of polyamine antimetabolites, an anticancer agent and a low-polyamine state. Two polyamine antimetabolites, given as either 40 mg/kg of methylglyoxal-bis-guanylhydrazone (MGBG) or ethylglyoxal-bis-guanylhydrazone (EGBG) and a normal diet (ND), or 20 mg/kg of each drug and a low polyamine diet (LPD), together with 1,000 mg/kg of alphadifluoromethylornithine (DFMO) were administered ip to nude mice for six consecutive days. Mitomycin C (MMC) at 2 mg/kg was then given ip for 3 alternate days. The combination of MGBG or EGBG with DFMO plus MMC resulted in an enhanced antitumor efficacy on LPD. However, the combination which included EGBG was much more enhanced than that which included MGBG and there was no evidence of any tumor regrowth. Weight loss was minimal or nil in the mice given the combination with EGBG, but was evident in those given the combination with MGBG. These results led to the conclusion that in mice, the combined therapy of EGBG with DFMO plus MMC and LPD is a safe and effective regimen for the treatment of gastric cancer.

Adenosylmethionine Decarboxylase↗
PubMed2006

Changes in free polyamine titers and expression of polyamine biosynthetic genes during growth of peach in vitro callus.

In the present paper, correlation between free polyamines and growth of peach (Prunus persica cv. Yuzora) in vitro callus was investigated. Growth of the callus was divided into three phases based on measurement of fresh weight. Free polyamines, putrescine (Put), spermidine (Spd), and spermine (Spm), could be detected during peach callus growth. Changes in free Put titers followed the callus growth rate, as shown by low and stable levels in the first stage, quick increase at the beginning of the second phase, and slow increase in the last phase, whereas fluctuations of Spd and Spm titers were aberrant from that of Put at early stage. Expressions of five key genes involved in polyamine biosynthesis were characterized, in which only the genes leading to Put synthesis, ADC (arginine decarboxylase) and ODC (ornithine decarboxylase), agreed with callus growth and fluctuation of Put titers. Treatment of the callus with D-arginine, an inhibitor of ADC, led to significant growth inhibition and enormous reduction of endogenous Put, coupled with obvious decrease of mRNA levels of ADC and ODC. Exogenous application of Put partially restored the callus growth, along with resumption of endogenous Put and expression levels of ADC and ODC. Spd and Spm titers experienced minor change in comparison to Put. The data presented here suggested that free Put played an important part in peach callus growth. Putative mechanisms or mode of action underlying the role of Put in peach callus growth and different expression patterns of the genes responsible for polyamine biosynthesis are also discussed.

Arginine↗
PubMed1991

The effects of polyamines and polyamine inhibitors on rat sciatic and facial nerve regeneration.

The effects of exogenous polyamines and polyamine biosynthetic pathway inhibitors on regenerating nerves were examined in adult male rats following nerve transection and surgical repair. Several studies have demonstrated the efficacy of exogenous polyamines in promoting the functional recovery of peripheral nerves following crush or freeze injuries in the rat. In order to simulate clinical peripheral nerve surgery, we studied these effects after complete nerve transection and evaluated regeneration by counting axons. There was no statistical difference in axon number with and without polyamines and in the presence of inhibitors and inhibitors with end product addition. Our study suggests that the difference in recovery seen in previous studies is not mediated by a change in axon number.

Animals↗
PubMed2000

Inhibition of polyamine oxidase enhances the cytotoxicity of polyamine oxidase substrates. A model study with N1-(n-octanesulfonyl)spermine and human colon cancer cells.

N(1)-(n-octanesulfonyl)spermine (N(1) OSSpm) is a substrate of polyamine oxidase. It shares several properties with spermine, such as antagonism of NMDA-type glutamate receptors, calmodulin antagonism, and cytotoxicity, but it is more potent by orders of magnitude in these regards than spermine. The human colon carcinoma-derived cell line CaCo-2 was used as a model to study the toxicity of N(1) OSSpm as a function of polyamine oxidase (PAO) activity and differentiation. If the formation of hydrogen peroxide and aminoaldehyde by the PAO-catalysed reactions was prevented by selective inactivation of the enzyme with MDL 72527, cytotoxicity of N(1)OSSpm was not diminished, but on the contrary, enhanced. Exponentially growing CaCo-2 cells were considerably more sensitive to N(1)OSSpm than differentiating cells. The results suggest that cytotoxic substrates of PAO exhibit enhanced cytotoxicity in cells, if PAO activity is inhibited. Since tumour cells are known to have lower polyamine oxidase activities than their normal counterparts, it will be interesting to explore whether cytotoxic substrates of polyamine oxidase, for which N(1)OSSpm is an example, are suited to preferentially kill tumour cells.

Apoptosis↗
PubMed1977

Polyamines and their biosynthetic enzymes in Ehrlich ascites-carcinoma cells. Modification of tumour polyamine pattern by diamines.

1. Ehrlich ascites-carcinoma cells contained relatively high concentrations of spermidine and spermine, but the putrescine content of the washed cells was less than 10% of that of higher polyamines. 2. Ascites-tumour cells likewise exhibited high activities of L-ornithine decarboxylase (EC 4.1.1.17), S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (EC 2.5.1.16) and spermine synthase. 3. During the first days after the inoculation, the polyamine pattern of the ascites cells was characterized by a high molar ratio of spermidine to spermine, which markedly decreased on aging of the cells. 4. Various diamines injected into mice bearing ascites cells rapidly and powerfully decreased ornithine decarboxylase activity in the carcinoma cells, apparently through a mechanism that was not a direct inhibition of the enzyme in vitro. Cadaverine (1,5-diaminopentane) and 1,6-diaminohexane were the most potent inhibitors of ornithine decarboxylase among the amines tested. 5. Chronic treatment of the mice with diamines resulted in a virtually complete disappearance of ornithine decarboxylase activity, and after 24h a significant decline in spermidine accumulation. 6. Cadaverine appeared to be an especially suitable compound for use as an inhibitor of the synthesis of higher polyamines, at least in Ehrlich ascites cells, since this diamine also acted as a competitive inhibitor for putrescine in the spermidine synthase reaction without being incorporated into the higher polyamines.

Adenosylmethionine Decarboxylase↗
PubMed1998

The identification of a cis-element and a trans-acting factor involved in the response to polyamines and polyamine analogues in the regulation of the human spermidine/spermine N1-acetyltransferase gene transcription.

The superinduction of spermidine/spermine N1-acetyltransferase (SSAT) gene has been associated with a cytotoxic response to a new class of antineoplastic polyamine analogues. The initial mechanism of SSAT superinduction is an increase in transcription in response to analogue exposure. This increased transcription appears to be modulated through the association between a nuclear protein factor and a cis-element described here as the polyamine-responsive element (PRE). The PRE was identified as a 9-base pair sequence, 5'-TATGACTAA-3', in the context of a 31-base pair stretch from -1522 to -1492 base pairs with respect to the SSAT transcriptional start site. This element binds a nuclear factor from polyamine analogue-responsive cells, but not from polyamine analogue-insensitive cells. The labeled PRE was used to clone and identify the transcription factor, Nrf-2, that binds constitutively to the PRE sequence. Although the PRE sequence shares homology to the originally identified Nrf-2 recognition sequence, the two sequences are not identical. The Nrf-2 transcription factor appears only to be present in cell types that are capable of expressing high amounts of SSAT. The results of these studies suggest that Nrf-2, bound to the PRE, plays an important regulatory role of expression of the human SSAT gene.

Acetyltransferases↗
PubMed2002

A polyamine analogue prevents acute pancreatitis and restores early liver regeneration in transgenic rats with activated polyamine catabolism.

We recently generated a transgenic rat model for acute pancreatitis, which was apparently caused by a massive depletion of pancreatic polyamines spermidine and spermine due to inducible activation of their catabolism (Alhonen, L., Parkkinen, J. J., Keinänen, T., Sinervirta, R., Herzig, K. H., and Jänne, J. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8290-8295). When subjected to partial hepatectomy, these animals showed striking activation of polyamine catabolism at 24 h postoperatively with a profound decrease in hepatic spermidine and spermine pools and failure to initiate liver regeneration. Here we show that pancreatitis in this model could be totally prevented, as judged by histopathology and plasma alpha-amylase activity, by administration of 1-methylspermidine, a metabolically stable analogue of spermidine. Similarly, the analogue, given prior to partial hepatectomy, restored early liver regeneration in the transgenic rats, as indicated by a dramatic increase in the number of proliferating cell nuclear antigen-positive hepatocytes from about 1% to more than 40% in response to the drug. The present results suggest that the extremely high concentration of spermidine in the pancreas, in fact the highest in the mammalian body, may have a critical role in maintaining organ integrity. The failure to initiate liver regeneration in the absence of sufficient hepatic polyamine pools similarly indicates that polyamines are required for proper commencement of the regenerative process.

Animals↗
PubMed2005

N1-aminopropylagmatine, a new polyamine produced as a key intermediate in polyamine biosynthesis of an extreme thermophile, Thermus thermophilus.

In the extreme thermophile Thermus thermophilus, a disruption mutant of a gene homologous to speB (coding for agmatinase = agmatine ureohydrolase) accumulated N1-aminopropylagmatine (N8-amidino-1,8-diamino-4-azaoctane, N8-amidinospermidine), a new compound, whereas all other polyamines produced by the wild-type strain were absent from the cells. Double disruption of speB and speE (polyamine aminopropyltransferase) resulted in the disappearance of N1-aminopropylagmatine and the accumulation of agmatine. These results suggested the following. 1) N1-Aminopropylagmatine is produced from agmatine by the action of an enzyme coded by speE. 2) N1-Aminopropylagmatine is a metabolic intermediate in the biosynthesis of unique polyamines found in the thermophile. 3) N1-Aminopropylagmatine is a substrate of the SpeB homolog. They further suggest a new biosynthetic pathway in T. thermophilus, by which polyamines are formed from agmatine via N1-aminopropylagmatine. To confirm our speculation, we purified the expression product of the speB homolog and confirmed that the enzyme hydrolyzes N1-aminopropylagmatine to spermidine but does not act on agmatine.

Agmatine↗
PubMed2002

Polyamine structural effects on the induction and stabilization of liquid crystalline DNA: potential applications to DNA packaging, gene therapy and polyamine therapeutics.

DNA undergoes condensation, conformational transitions, aggregation and resolubilization in the presence of polyamines, positively charged organic molecules present in all cells. Under carefully controlled environmental conditions, DNA can also transform to a liquid crystalline state in vitro. We undertook the present work to examine the ability of spermidine, N4-methylspermidine, spermine, N1-acetylspermine and a group of tetramine, pentamine and hexamine analogs of spermine to induce and stabilize liquid crystalline DNA. Liquid crystalline textures were identified under a polarizing microscope. In the absence of polyamines, calf thymus DNA assumed a diffused, planar cholesteric phase with entrapped bubbles when incubated on a glass slide at 37 degrees C. In the presence of spermidine and spermine, the characteristic fingerprint textures of the cholesteric phase, adopting a hexagonal order, were obtained. The helical pitch was 2.5 micro m. The final structures were dendrimeric and crystalline when DNA was treated with spermine homologs and bis(ethyl) derivatives. A cholesteric structure was observed when DNA was treated with a hexamine at 37 degrees C. This structure changed to a hexagonal dendrimer with fluidity on prolonged incubation. These data show a structural specificity effect of polyamines on liquid crystalline phase transitions of DNA and suggest a possible physiological function of natural polyamines.

Animals↗
PubMed1981

Decrease in the S1 protein of 30-S ribosomal subunits in polyamine-requiring mutants of Escherichia coli grown in the absence of polyamines.

The reason for the decrease of polypeptide-synthetic activity of 30-S ribosomal subunits obtained from two polyamine-requiring mutants of Escherichia coli, grown in the absence of polyamines, has been studied by analyzing the total and split proteins of 30-S subunits by disc gel and slab gel electrophoresis. It was concluded that the decrease of S1 protein in 30-S subunits was responsible for the decrease of polypeptide synthesis in polyamine-requiring mutants of E. coli grown in the absence of polyamines.

Electrophoresis, Polyacrylamide Gel↗
PubMed1992

The role of protonation and conformational transition of polyamine grafts in platelet retention to polyamine-graft-PHEMA copolymer surfaces.

Blood platelet retention on polyamine-graft-poly(2-hydroxyethyl methacrylate) (PHEMA) copolymer (HA) surface was investigated, focusing on pH and ionic strength of the surrounding medium to elucidate the nature of ionic interaction between platelets and HA copolymer surfaces. The conformational transition of polyamine graft chain in response to the protonation degree of amino groups was demonstrated to be an important factor influencing platelet retention on HA surfaces. When the polyamine graft chain exists in an extended conformation, protonated amino groups distribute from the matrix interface into the aqueous interior, resulting in the effective ionic interaction with platelets to increase their retention on HA copolymer surfaces. The number of protonated amino groups in polyamine portions crucially affected platelet retention. Worth noticing is that an introduction of a small but definite amount of cationic sites on the polymer surface led to significantly minimized platelet retention. It is considered that the surface property of PHEMA was drastically changed to a non-adhesive surface by introducing a small amount of protonated amino groups.

Animals↗
PubMed1999

Polyamine-fas interactions: inhibition of polyamine biosynthesis in MRL-lpr/lpr mice is associated with the up-regulation of fas mRNA in thymocytes.

MRL-lpr/lpr is a strain of mice that develops spontaneous signs of the autoimmune disease, systemic lupus erythematosus (SLE or lupus). The lpr (lymphoproliferation) defect has been identified as an insertion of an early transposon (ETn) derived sequence into the fas apoptosis gene. We studied the in vivo effects of difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), on the expression of fas in MRL-lpr/lpr mice as well as in congenic MRL- + / + and autoimmune NZB/W strains. Using Northern blot hybridization and reverse transcription polymerase chain reaction (RT-PCR), we found that DFMO treatment resulted in an increase in the expression of fas mRNA in the thymus of MRL-lpr/lpr mice. Using RT-PCR, we further found that the increased expression of fas was associated with the suppression of chimeric ETn/fas mRNA. With fractionated CD4 + and CD8 + T cells, we found a cell-specific effect of DFMO on chimeric ETn/fas expression in CD8 + cells. ETn/fas expression was detected in CD8+ T cells from untreated mice, but it was eliminated after DFMO treatment. HPLC analysis of polyamines showed depletion of putrescine and partial reduction of spermidine (35%) in DFMO-treated mice compared to controls. These results indicate that DFMO-mediated polyamine depletion is linked to the regulation of fas and chimeric ETn/fas in MRL-lpr/lpr mice. Elevated levels of polyamines in this strain, as found in earlier studies, may be associated with the progression of the autoimmune disease by altering the expression of fas gene or by facilitating the expression of chimeric ETn/fas. Our data also provide new mechanistic insights into the beneficial effects of DFMO on these mice.

Animals↗
PubMedDate not supplied

Are polyamines involved in the contractile effects of angiotensin II in the rat aorta? (Polyamines and angiotensin II in rat aorta).

Angiotensin II (AII) is a central factor involved in the pathophysiology of arterial hypertension and atherosclerosis. On the other hand, polyamines represent a family of organic cations with low molecular weight, playing intracellular regulatory roles essential for the cellular growth and differentiation. The cellular contents, the synthesis and the transport of polyamines are increased following the actions of AII, as well as of other cellular growth factors. Our results show that the administration of polyamines as pre-treatment modulates the contractile effects of extracellular AII (80 nM). This modulation is concentration-dependent and dual: the lower concentrations amplify and the higher concentrations reduce the effects of AII in the isolated rat aorta rings without endothelium. Moreover, DL-alpha-Difluoromethylomithine (DFMO), a specific inhibitor of ornithine decarboxylase, does not significantly modify the contractile effects of AII. Thus, these data suggest that polyamines generated through this metabolic pathway are not involved in the contractile effects of AII in rat aortic vascular smooth muscle.

Angiotensin II↗
PubMed1991

Prostatic polyamines and polyamine targeting as a new approach to therapy of prostatic cancer.

The prostate is a rich factory of polyamine production. In spite of this, the prostate is also able to accumulate polyamines from the circulation. Intracellular polyamine depletion has been observed to enhance the accumulation of diamines such as putrescine. This needs to be taken advantage of either as a means for imaging prostatic tumour spread to the lymph nodes or as a means of targeting toxins to the prostatic tumour. Putrescine is a small molecule that may prove difficult for use for synthesizing stable toxin derivatives that can take advantage of the targeting potential of the polyamine transporter. The cloning and sequencing characterization of the transporter is under way. When the prostatic transporter is identified, it will be possible to understand the role of the transporter in normal and cancerous prostatic cell growth and functioning and should serve to aid our understanding of how we can better optimize agents to use the transporter for delivery of antitumour agents.

Aziridines↗
PubMed1986

[Detection of urinary polyamine by a new enzymatic differential assay. (III). Studies on urinary polyamines in patients with malignant genitourinary diseases].

A new enzymatic method for isolation and determination of urinary polyamines was presented and basically studied in previous report 1 and 2 in comparison with existing techniques. Using the new method, urinary polyamines were isolated and determined in 56 patients with genitourinary cancer. Urinary polyamines were also determined in 63 controls consisting of 20 normal subjects, 25 patients with benign urological disease and 18 patients with BPH. The mean concentrations of Diamine, Spermidine, Spermine in 20 normal subjects were 16.6 +/- 5.8 mumoles/g Cr, 4.7 +/- 2.0 mumoles/g Cr and 0.99 +/- 0.51 mumoles/g Cr respectively. To emphasize the specificity to cancer, the level of positiveness was modified to a higher value than M+3SD. The positive values thus calculated were 40 mumoles/g Cr for Diamine, 15 mumoles/g Cr for Spermidine and 3 mumoles/g Cr for Spermine. The positive ratios of Diamine in patients with early cancer were 43% in renal cell cancer, 20% in pelvic and ureter cancer, 0% in bladder cancer and 20% in prostatic cancer. Those of Spermidine were 29% in renal cell cancer, 0% in pelvic and ureter cancer, 20% in bladder cancer and 40% in prostatic cancer. Those of Spermine were 29% in renal cell cancer, 20% in pelvic and ureter cancer, 20% in bladder cancer and 0% in prostatic cancer. In early diagnoses, Diamine indicated high positive ratios to renal cell cancer and Spermidine to prostatic cancer. Relatively high positive ratios were demonstrated, when any one of the isolated polyamines was found positive: namely, 57% in renal cell cancer, 20% in pelvic and ureter cancer, 30% in bladder cancer and 40% in prostatic cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Diamines↗
PubMed1986

[Detection of polyamines by a new enzymatic differential assay. (5). Studies on polyamine in the blood of patients with malignant genitourinary diseases].

Using the new enzymatic assay for isolation and determination of polyamine in blood presented in Report 4, the polyamines in the blood were isolated and determined in 84 patients with genitourinary cancer. In the early diagnosis, the positive rates of each fraction were not so high, but, relatively high positive rates were demonstrated, when any one of the polyamines were found positive: namely, 85.7% in renal cell cancer, 66.7% in renal pelvic and ureteral cancer, 44.0% in bladder cancers. These results seem to support the usefulness of the new method, and encourage further investigation of polyamines in the blood as tumor markers.

Diamines↗