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PubMed1997

Comparative molecular field analysis-based predictive model of structure-function relationships of polyamine transport inhibitors in L1210 cells.

Maintenance of intracellular polyamine concentrations necessary for cell growth and proliferation is regulated in part by an energy-dependent polyamine uptake system. To obtain information on the characteristics of the polyamine uptake system in L1210 leukemia cells, we have applied computational chemistry techniques to the study of relationships between structure and function of 57 polyamine analogues. Ki values of polyamine analogues, derived from competitive inhibition of [3H]spermidine transport into L1210 cells, were chosen as the measure of biological activity. Using comparative molecular field analysis (CoMFA), a model was constructed to relate molecular structure with biological activity. The model was based on 4 monocationic, 8 dicationic, 14 tricationic, and 20 tetracationic polyamine analogues with a range of Ki values for the inhibition of [3H]spermidine uptake of 0.97-521 microM. The CoMFA model successfully predicted the inhibitory potency of 11 polyamines that had not previously been tested for polyamine uptake inhibitory activity. The 11 values predicted were within 33 +/- 62% of the actual Ki values. The test group included aziridinyl diamines, acetylated spermidines, two new oxazolidinonyl spermidines, monoaziridinyl spermidines, and a diaziridinyl spermine. Several of the compounds from this test group have been shown to have anticancer activity in mice. Consistent with the CoMFA model, certain basic functional groups, such as aziridines that have pKa values in the range of 6-7, seem to interact with the polyamine transporter in a cationic form. The results suggest that the CoMFA model is useful in drug design strategies as a predictive tool for the discovery of new anticancer agents that utilize a polyamine transporter for cellular uptake.

Animals↗
PubMed1996

Effect of phytohaemagglutinin on intestinal cell proliferation. Role of polyamines.

The polyamines, putrescine, spermidine and spermine, mediate the effects of hormones and growth factors as second messengers. They are necessary for every step of protein, RNA and DNA synthesis and are therefore essential for cell growth and proliferation. As with hormones and peptide growth factors, plant lectins which bind to cell surface receptors of the brush border membrane are powerful extraneous growth factors for the gut and as a result, by interacting with brush border epithelial receptors, induce extensive proliferation and changes in the metabolism of epithelial cells via activation of second messenger pathways. In model experiments with phytohaemagglutinin (PHA, the lectin from the kidney bean, Phaseolus vulgaris) it was shown that lectins which bind avidly to the mucosal surface induce dose- and time-dependent and fully reversible hyperplastic and hypertrophic growth of the small bowel. The resulting increase in crypt cell proliferation (CCPR) alters the gene expression in epithelial cells. These metabolic changes require vast amounts of polyamines, mostly spermidine. Thus, one of the first effects of the PHA signal is to stimulate the basolateral polyamine uptake system for the sequestration of polyamines from blood circulation in sufficient amounts to sustain the growth of the tissue. Our data indicate that the main source of polyamines to replenish those taken up by the gut is the diet. It has been shown repeatedly that, because of intensive cell proliferation, tumour growth requires large amounts of polyamines. PHA or other lectins accelerate normal metabolic reactions in a regulated way while maintaining their full reversibility and without causing irreversible aberrations. The fact that the lectin-induced growth of the gut requires large amounts of polyamines, suggests that lectins are ideal agents to limit the availability of polyamines for unwanted growth such as neoplastic proliferation of tumours. Accordingly, it may be possible to limit the availability of polyamines for tumour growth by inducing a competitive, but fully reversible, controlled growth of the gut tissue. The intensively but reversibly growing gut tissues can slow down tumour growth by sequestering polyamines and nutrients from circulation.

Animals↗
PubMed2000

Circular dichroism and NMR studies of metabolically stablealpha-methylpolyamines: spectral comparison with naturally occurring polyamines.

Three synthetic polyamine analogs, alpha-methylspermine, and alpha,alpha'-dimethylspermine, were compared with their naturally occurring counterparts, spermidine and spermine, by two different spectral techniques. The interaction of polyamines with oligodeoxynucleotides was measured by circular dichroism in order to monitor the polyamine-induced conversion of right-handed B-DNA to the left-handed Z-form. The methylated analogs were shown to be equally effective as the natural polyamines in inducing the B --> Z transition. The pH dependence of the chemical shift of all carbon atoms in each of the five polyamines was measured by (13)C-NMR spectroscopy. With the exception of expected changes in chemical shift due to the presence of the alpha-methyl substituents, the chemical shifts and pH dependence of all carbon atoms in the three alpha-methyl polyamines were similar to the corresponding naturally occurring polyamines. The combined data indicate that alpha-methyl polyamines have physical properties that are very similar to their natural counterparts. The two metabolically stable polyamine analogs, alpha-methylspermidine and alpha,alpha'-dimethylspermine, are therefore useful surrogates for spermidine and spermine in the study of numerous polyamine-mediated effects in mammalian cell cultures and can be used in such studies without the requirement for coadministration of amine oxidase inhibitors.

Journal Article↗
PubMed1987

Polyamine uptake in carrot cell cultures.

Putrescine and spermidine uptake into carrot (Daucus carota L.) cells in culture was studied. The time course of uptake showed that the two polyamines were very quickly transported into the cells, reaching a maximum absorption within 1 minute. Increasing external polyamine concentrations up to 100 millimolar showed the existence of a biphasic system with different affinities at low and high polyamine concentrations. The cellular localization of absorbed polyamines was such that a greater amount of putrescine was present in the cytoplasmic soluble fraction, while spermidine was mostly present in cell walls. The absorbed polyamines were released into the medium in the presence of increasing external concentrations of the corresponding polyamine or Ca(2+). The effects of Ca(2+) were different for putrescine and spermidine; putrescine uptake was slightly stimulated by 10 micromolar Ca(2+) and inhibited by higher concentrations, while for spermidine uptake there was an increasing stimulation in the Ca(2+) concentration range between 10 micromolar and 1 millimolar. La(3+) nullified the stimulatory effect of 10 micromolar Ca(2+) on putrescine uptake and that of 1 millimolar Ca(2+) on spermidine uptake. La(3+) at 0.5 to 1 millimolar markedly inhibited the uptake of both polyamines, suggesting that it interferes with the sites of polyamine uptake. Putrescine uptake was affected to a lesser extent by metabolic inhibitors than was spermidine uptake. It is proposed that the entry of polyamines into the cells is driven by the transmembrane electrical gradient, with a possible antiport mechanism between external and internal polyamine molecule.

Journal Article↗
PubMed1994

Effects of metal treatment on DNA repair in polyamine-depleted HeLa cells with special reference to nickel.

Human cells depleted of the naturally occurring polyamines putrescine, spermidine, and spermine exhibit altered chromatin structure and marked deficiencies in DNA replicative and repair processes. Similar effects have been observed following treatment of normal mammalian cells with various heavy metal salts. In an attempt to better understand how metals interfere with normal DNA metabolic processes, a series of studies was carried out in which the toxicity and repair-inhibitory properties of various metals were evaluated in polyamine-depleted HeLa cells. Cytotoxicity of copper, zinc, magnesium, and cadmium was not altered in cells carrying lower polyamine pools. However, the sensitivity to nickel was markedly increased upon polyamine depletion, a condition that was readily reversed by polyamine supplementation. Nucleoid sedimentation analysis indicated that a greater amount of nickel-induced DNA damage occurred in polyamine-depleted cells than in normal cells, possibly serving as the basis for the increased sensitivity. Both polyamine depletion and nickel treatment result in decreased repair of DNA strand breaks and decreased cloning efficiency following X-ray and ultraviolet irradiation. Nickel treatment of polyamine-depleted cells resulted in synergistic sensitivity to both radiation treatments. None of the other metals tested enhanced X-ray or ultraviolet sensitivity of polyamine-depleted cells. Analysis of retarded repair sites following ultraviolet irradiation indicated those sites to be nonligatable in polyamine-depleted and nickel-treated cells, suggesting a block in the normal gap-sealing process.

DNA Repair↗
PubMed2003

Polyamine metabolism in primary human colon adenocarcinoma cells (SW480) and their lymph node metastatic derivatives (SW620).

The natural polyamines are multifunctional constituents of all eucaryotic cells. The objective of this work was to compare aspects of polyamine metabolism in two related cell lines with the idea to investigate whether metabolic differences can be attributed to functional differences of the cells. The human colon carcinoma-derived cell lines SW480 and SW620 were chosen as models. SW480 cells were isolated from the primary tumour, SW620 cells from a lymph node of the same patient. SW620 cells grow faster, and the key regulatory enzymes of polyamine biosynthesis (ODC and AdoMetDC) are more active in the metastatic cells. Moreover, their ability to accumulate polyamines from the environment is more important than of SW480 cells. Likewise polyamine concentrations were markedly higher in SW620 cells, although they are much smaller than SW480 cells, and have a particularly small cytoplasmic space. Both cell lines show a striking diminution of ODC and AdoMetDC activities and changes in the polyamine patterns at the transition from exponential to non-exponential growth--most probably as a consequence of high cell density. Depletion of putrescine and spermidine due to inactivation of ODC by DFMO causes accumulation of cells in G1, and a proportional decrease of S-phase cells in both cell lines. Based on morphologic and other criteria SW480 and SW620 cells were typified as poorly differentiated. In agreement with their low grade of differentiation they exhibit a low alkaline phosphatase activity. However, the time-dependent decrease of alkaline phosphatase is not typical of differentiation patterns of other adenocarcinoma-derived cell lines or of normal enterocytes. The high capacity of de novo polyamine biosynthesis and of polyamine uptake is presumably a prerequisite for the rapid growth and invasiveness. The fact that these properties were more accentuated in the case of SW620 cells and paralleled enhanced metastatic properties indicate relationships between basic parameters of polyamine metabolism and malignancy.

Adenocarcinoma↗
PubMed2001

Human DNA topoisomerase I inhibitory activities of synthetic polyamines: relation to DNA aggregation.

DNA aggregation by polyamines has acquired importance as a prerequisite for the cellular uptake of DNA for gene therapy. Intracellular polyamines are constitutive components of mammalian cells and their availability is critical for cell proliferation. Interference of polyamine biosynthesis by synthetic polyamines leads to cytotoxicity. Optimization of the polyamine structural parameters is necessary to control their DNA aggregation, cytotoxic or enzyme inhibitory activities. We designed two series of tetra- and hexamines and compared their human DNA topoisomerase I (top1) inhibitory effects with the DNA aggregation properties. We show that hexamines are more efficient inhibitors of DNA relaxation by top1 than tetramines and that they suppress the top1-mediated DNA cleavage while tetramines do not. The DNA aggregation abilities within two series of polyamines correlate with the length of their central methylene chain. By contrast, the top1 inhibition within two series does not show the same correlation but demonstrates a threshold inhibitory effect on going from the (CH(2))(12) to the (CH(2))(14) central chain. We show further that the structures of DNA aggregates formed by polyamines with the (CH(2))(10-12) or with the (CH(2))(14-16) chains are very different. The first are a fluid cholesteric-type phases, whereas the second are well-structured aggregates similar to columnar liquid crystals with high packing density of DNA duplexes. The structures of polyamines-induced DNA aggregates are proposed to be crucial for top1 catalysis. The structure-function correlation described here may serve as a guide for rational design of polyamines with desired DNA-aggregation or anti-top1 activities.

Base Sequence↗
PubMed2003

Polyamine analogues as anticancer drugs.

Just over 30 years ago, the late Diane Russell published the first in a series of papers linking polyamines and cancer. These early studies led to a flurry of research activity in the polyamine field that continues to this day attempting to identify a role for the polyamines in cancer development, treatment and/or prevention. The recognition that polyamines are critical for the growth of cancer cells, and consequently the identification of their metabolic pathways as a target for therapeutic intervention, led to the development of a number of useful inhibitors of polyamine biosynthesis. Arguably the most significant addition to the polyamine field in the last 30 years was the synthesis of alpha-difluoromethylornithine (DFMO), which is being tested currently as a cancer chemopreventative agent in man and is used also as a highly effective trypanocidal agent. Although an extremely useful tool experimentally, DFMO has been disappointing in clinical trials with little therapeutic efficacy. Despite this setback, the polyamine pathway is still considered a viable target for chemotherapeutic intervention. This has led to the development of the polyamine analogues as multifunctional inhibitors that will produce inhibition of tumour cell growth, polyamine depletion and optimum therapeutic efficacy.

Antineoplastic Agents↗
PubMed2004

Ectopic expression of maize polyamine oxidase and pea copper amine oxidase in the cell wall of tobacco plants.

To test the feasibility of altering polyamine levels by influencing their catabolic pathway, we obtained transgenic tobacco (Nicotiana tabacum) plants constitutively expressing either maize (Zea mays) polyamine oxidase (MPAO) or pea (Pisum sativum) copper amine oxidase (PCuAO), two extracellular and H(2)O(2)-producing enzymes. Despite the high expression levels of the transgenes in the extracellular space, the amount of free polyamines in the homozygous transgenic plants was similar to that in the wild-type ones, suggesting either a tight regulation of polyamine levels or a different compartmentalization of the two recombinant proteins and the bulk amount of endogenous polyamines. Furthermore, no change in lignification levels and plant morphology was observed in the transgenic plants compared to untransformed plants, while a small but significant change in reactive oxygen species-scavenging capacity was verified. Both the MPAO and the PCuAO tobacco transgenic plants produced high amounts of H(2)O(2) only in the presence of exogenously added enzyme substrates. These observations provided evidence for the limiting amount of freely available polyamines in the extracellular space in tobacco plants under physiological conditions, which was further confirmed for untransformed maize and pea plants. The amount of H(2)O(2) produced by exogenously added polyamines in cell suspensions from the MPAO transgenic plants was sufficient to induce programmed cell death, which was sensitive to catalase treatment and required gene expression and caspase-like activity. The MPAO and PCuAO transgenic plants represent excellent tools to study polyamine secretion and conjugation in the extracellular space, as well as to determine when and how polyamine catabolism actually intervenes both in cell wall development and in response to stress.

Amine Oxidase (Copper-Containing)↗
PubMedDate not supplied

Inhibition of polyamine oxidase improves the antitumoral effect of ornithine decarboxylase inhibitors.

Specific inhibition of ornithine decarboxylase activity prevents the formation of putrescine from ornithine and decreases spermidine levels of slow-growing organs by about 20%. However, spermidine levels of rapidly growing tissues, such as tumors, may under the same conditions be decreased by as much as 60%. Inactivation of polyamine oxidase prevents oxidative splitting of N1-acetylspermidine and N1-acetylspermine and therefore the reutilization of putrescine for de novo polyamine biosynthesis. Prolonged inhibition of ornithine decarboxylase and polyamine oxidase activities leads in all normal tissues studied so far to a decrease of the spermidine concentration by 50% or more, demonstrating the general physiological significance of polyamine reutilization. In this work the role of polyamine reutilization in tumors was studied. Combined treatment with the inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine or (2R, 5R)-6-heptyne-2,5-diamine, and N1, N4-bis-allenylputrescine, an inhibitor of polyamine oxidase, produced a more marked depletion of the polyamine contents of L1210 ascitic cells and of Lewis lung carcinoma, than treatment with either compound alone. Concomitantly, the proliferative activity of these tumors decreased significantly below the value that was observed after treatment with an ornithine decarboxylase inhibitor alone. Our results demonstrate that polyamines which are produced by the interconversion pathway are used by the tumors in order to cover their polyamine requirement.

Alkynes↗
PubMed1981

Interconversion, catabolism and elimination of the polyamines.

Two catabolic pathways exist for spermidine and spermine. One is responsible for the interconversion of the polyamines, a physiological intracellular event. The first and probably rate limiting step of the polyamine interconversion pathway is acetylation in the N1-position by a cytosolic enzyme. The reaction products N1-acetylspermine and N1-acetylspermidine are substrates of the cytoplasmic polyamine oxidase. This enzyme transforms the N1-acetylpolyamines into spermidine and putrescine respectively. N1-Acetylspermidine is at the same time a major urinary excretion product. The factors which control the rates of N1-acetylspermidine degradation by polyamine oxidase versus its elimination via transport are not known. The second catabolic pathway forms putreanine from spermidine and N8-(2-carboxyethyl)-spermidine and spermic acid from spermine. It is catalyzed by the well known serum spermine oxidase. The second step in this reaction sequence, the dehydrogenation of the aldehydes formed by the serum spermine oxidase occurs intracellularly and is catalyzed either by specific or non-specific aldehyde dehydrogenases. The function of this "two compartment reaction sequence" is most probably to protect tissues from extracellular or exogenous (alimentary) polyamines. Its end-products appear to be physiologically indifferent urinary excretion products. Both catabolic pathways may have marked effects on the urinary polyamine pattern. Drugs as well as a variety of physiological and pathological states may influence polyamine catabolism and elimination at various levels, and may cause characteristic alterations in the urinary excretion of free and conjugated polyamines and of the amino acids deriving from the polyamines.

Acetylation↗
PubMed1996

Mucosal polyamine measurements and colorectal cancer risk.

Polyamines are short-chain aliphatic amines required for normal cellular growth that are ubiquitously found in all living tissues. Polyamine content has been shown to correlate with cellular proliferation. Quantitation of polyamines may thus provide a biochemical measure of proliferation in the colorectal mucosa where dysregulated epithelial proliferation is associated with colorectal cancer risk. A case-control study was conducted to validate the hypothesized association between mucosal polyamine measurements and colorectal cancer risk. Polyamines were measured in 4-6 multiple rectal mucosal biopsies from 11 normal control subjects and seven case patients with colon cancer. Compared with the controls, mean polyamine measurements, after adjustment for age and sex, were significantly increased for spermidine (P < 0.003) and spermine (P < 0.017). Subsequent analysis indicated that in controls 1-4 biopsies appeared adequate to characterize an individual. However, mucosal polyamines in the cases exhibited more sampling variability, requiring 4-8 biopsies to achieve an acceptable level of reliability. After adjustment for age and sex, the odds ratios for spermidine and spermine levels, compared to the controls, were 4.8 (95% confidence interval: 1.6-33.7) and 2.3 (1.2-6.3), respectively. The results of this study indicate that increases of mucosal polyamine measurements, after taking the sampling and methodological variability into account, are significantly associated with colorectal cancer risk, and suggest that polyamine measurements in rectal mucosa may play an important role as biomarkers for identifying high-risk individuals and/or for using as intermediate endpoints in prevention trials.

Aged↗
PubMed1998

Polyamines may regulate S-phase progression but not the dynamic changes of chromatin during the cell cycle.

Several studies suggest that polyamines may stabilize chromatin and play a role in its structural alterations. In line with this idea, we found here by chromatin precipitation and micrococcal nuclease (MNase) digestion analyses, that spermidine and spermine stabilize or condense the nucleosomal organization of chromatin in vitro. We then investigated the possible physiological role of polyamines in the nucleosomal organization of chromatin during the cell cycle in Chinese hamster ovary (CHO) cells deficient in ornithine decarboxylase (ODC) activity. An extended polyamine deprivation (for 4 days) was found to arrest 70% of the odc- cells in S phase. MNase digestion analyses revealed that these cells have a highly loosened and destabilized nucleosomal organization. However, no marked difference in the chromatin structure was detected between the control and polyamine-depleted cells following the synchronization of the cells at the S-phase. We also show in synchronized cells that polyamine deprivation retards the traverse of the cells through the S phase already in the first cell cycle. Depletion of polyamines had no significant effect on the nucleosomal organization of chromatin in G1-early S. The polyamine-deprived cells were also capable of condensing the nucleosomal organization of chromatin in the S/G2 phase of the cell cycle. These data indicate that polyamines do not regulate the chromatin condensation state during the cell cycle, although they might have some stabilizing effect on the chromatin structure. Polyamines may, however, play an important role in the control of S-phase progression.

Animals↗
PubMed1999

Topoisomerase II is nonfunctional in polyamine-depleted cells.

The polyamines-putrescine, spermidine, and spermine-are essential for normal cell proliferation. Polyamine depletion affects DNA structure and synthesis. Topoisomerase II (topo II) is also necessary for normal cell proliferation, and it has been shown in vitro that polyamines may affect topo II activity. In order to investigate the effect of polyamine depletion on topo II activity, we treated Chinese hamster ovary cells with either alpha-difluoromethylornithine (DFMO) or 4-amidinoindan-1-one-2'-amidinohydrazone (CGP 48664), which are polyamine biosynthesis inhibitors. Treatment with the topo II inhibitor etoposide results in DNA strand breaks only if there is active topo II in the cells. By quantitating DNA strand breaks after etoposide treatment using single cell gel electrophoresis, we were able to estimate intracellular topo II activity. We also quantitated topo II activity in crude nuclear extracts from control and polyamine biosynthesis inhibitor-treated cells. Using single cell gel electrophoresis, we noted a clear decrease in the function of topo II in polyamine biosynthesis inhibitor-treated cells, as compared with untreated control cells. However, the topo II activity in crude nuclear extracts did not differ significantly in control versus polyamine biosynthesis inhibitor-treated cells. Taken together, these results indicate that although the function of topo II in polyamine-depleted cells was impaired, topo II remained functional in an in vitro assay. Using the single cell gel electrophoresis assay, we also found that spermine depletion itself caused DNA strand breaks.

Adenosylmethionine Decarboxylase↗
PubMed2001

Assessment of the capillary zone electrophoretic behavior of proteins in the presence of electroosmotic modifiers: protein-polyamine interaction studied using a polyacrylamide-coated capillary.

The use of polyamines as electroosmotic modifiers has been shown to be effective in enhancing resolution of protein glycoforms in capillary zone electrophoresis (CZE) using a bare capillary tube. In this study, effectiveness was evaluated by using a polyacrylamide-coated capillary tube instead of a bare capillary tube. Electropherograms obtained in the presence of polyamines were inferior to those obtained in their absence with respect to resolution. Electrophoretic mobility of the proteins decreased and their peaks were broadened by polyamines bound to them. This unfavorable effect was dependent on both the species of polyamines and the pH values of the electrolyte buffer. The reduction of resolution caused by polyamines was in the following order: spermidine (SPD) approximately spermidine-tri-hydrochloride (SPD-HCI) > putrescine (PUT) > hexamethonium chloride (HMC). The observed effect can be ascribed to the formation of complexes between the proteins and the polyamines. In addition, for the bare capillary tube the complexes showed interaction with the inner surface, resulting in local suppression of electroosmosis and poor resolution. The high resolution obtained in the coated capillary tube was reduced in the presence of the polyamines. Thus, the use of the polyamines has a negative effect on the analysis of protein microheterogeneity as a result of protein-polyamine interaction.

Acrylic Resins↗
PubMed2004

Molecular dynamics simulation study of oriented polyamine- and Na-DNA: sequence specific interactions and effects on DNA structure.

Molecular dynamics (MD) computer simulations have been carried out on four systems that correspond to an infinite array of parallel ordered B-DNA, mimicking the state in oriented DNA fibers and also being relevant for crystals of B-DNA oligonucleotides. The systems were all comprised of a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charges. The sequence of the double helical DNA decamer was d(5'-ATGCAGTCAG)xd(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine(3+) (Spd(3+)) and putrescine(2+) (Put(2+)), the synthetic polyamine diaminopropane(2+) (DAP(2+)), and the simple monovalent cation Na(+). This work compares the specific structures of the polyamine- and Na-DNA systems and how they are affected by counterion interactions. It also describes sequence-specific hydration and interaction of the cations with DNA. The local DNA structure is dependent on the nature of the counterion. Even the very similar polyamines, Put(2+) and DAP(2+), show clear differences in binding to DNA and in effect on hydration and local structure. Generally, the polyamines disorder the hydration of the DNA around their binding sites whereas Na(+) being bound to DNA attracts and organizes water in its vicinity. Cation binding at the selected sites in the minor and in the major groove is compared for the different polyamines and Na(+). We conclude that the synthetic polyamine (DAP(2+)) binds specifically to several structural and sequence-specific motifs on B-DNA, unlike the natural polyamines, Spd(3+) and Put(2+). This specificity of DAP(2+) compared to the more dynamic behavior of Spd(3+) and Put(2+) may explain why the latter polyamines are naturally occurring in cells.

Base Sequence↗
PubMed1985

Hormone-independent polyamine metabolism of squamous cell carcinoma of the prostate.

The levels of polyamines and their synthesizing enzymes in squamous cell carcinoma of prostate implanted in intact as well as castrated male rats were determined after certain hormonal manipulations. The tumour was found to grow with an identical rate in non-castrated and castrated rats. Polyamine content and activities of polyamine synthesizing enzymes in the tumour were found to be much lower compared to their values in ventral prostate. Moreover, the levels of these parameters were comparable in tumours whether implanted in non-castrated or gonadectomized animals. The sequential analyses of putrescine and spermidine and activities of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase of tumours at different time intervals showed a significant reduction in their levels at 30 days compared to 10 days post implantation in non-castrated as well as castrated rats. Daily intramuscular administration of tumour-bearing intact or castrated animals with testosterone (50 micrograms/g), beta-estradiol (2 micrograms/g) or cyproterone (12.5 micrograms/g) for 10 days did not influence polyamine metabolism in tumour tissue. However, either beta-estradiol and cyproterone treatments or castration were found to decrease polyamine synthesis in ventral prostate. At the same time, the testosterone replacement therapy did not allow polyamine levels or activities of polyamine synthesizing enzymes to decline in the ventral prostate of castrated rats. Our results demonstrated that contrary to ventral prostate, the polyamine metabolism in squamous cell carcinoma of prostate is independent of hormonal control. The loss of hormonal sensitivity of polyamine metabolism in the prostatic tumour could be the result of qualitative changes that occurred during transformation.

Adenosylmethionine Decarboxylase↗
PubMed1995

Polyamines as biomarkers of cervical intraepithelial neoplasia.

Polyamines (putrescine, spermidine and spermine) play critical roles in cell growth and transformation. Ornithine decarboxylase (ODC), key enzyme in polyamine biosynthesis, is considered a putative protooncogene crucial to the regulation of cell growth and transformation. Cancer patients have elevated levels of polyamines in their physiological fluids compared to normal counterparts. alpha-Difluoromethylornithine (DFMO), a specific suicide inhibitor of ODC, exhibits antitumor and antimetastasis activities, and displays effectiveness in many carcinogen-induced animal chemoprevention models. Therefore, we are using DFMO in a chemoprevention trial for cervical intraepithelial neoplasia grade III (CIN III), and evaluating patients for changes in polyamine metabolism as an intermediate marker of DFMO effect. A preliminary study showed that several milligrams of abnormal cervical biopsy tissue contained detectable levels of ODC activity and polyamines. Additionally, the presence of cadaverine suggested bacterial contamination of these tissues. For this reason, normal and abnormal biopsies collected during colposcopy were rinsed prior to frozen storage. In most patients, abnormal tissue showed greater ODC activities and lower spermidine/spermine ratios than normal tissues. Patients are now being treated with de-escalating doses of DFMO (1-0.06 g/m2/day) for one month. To study the effect of DFMO in patients with CIN III, we are collecting blood and cervical tissue specimens to measure the following parameters: plasma DFMO, ornithine and arginine levels; plasma N1-acetylspermidine levels; erythrocyte (blood polyamine carrier) free polyamine levels; cervical tissue free polyamine levels; cervical tissue N1-acetylspermidine levels; and cervical tissue ODC activities. N1-acetylspermidine will be examined as this compound is known to exist primarily in tumor tissues, not in normal tissues. We therefore established a high-performance liquid chromatography method for N1-acetylspermidine. We expect to find that polyamines are effective markers in analyzing DFMO effects in this chemoprevention trial, thus functioning as pharmacodynamic parameters as well as biomarkers for transformation.

Biogenic Polyamines↗