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PubMed2001

Polyamine metabolism in brain tumours: diagnostic relevance of quantitative biochemistry.

OBJECTIVE: Activation of polyamine metabolism is closely associated with cellular proliferation. The purpose was to investigate whether the content of the polyamines putrescine, spermidine, and spermine, and the activity of the first metabolic key enzyme of polyamine metabolism, ornithine decarboxylase (ODC), represent biochemical markers of malignancy in brain tumours. METHODS: The concentration of putrescine, spermidine, and spermine, and the activity of ODC were biochemically quantified in tissue samples obtained during open microsurgery of 670 patients with brain tumours. Biochemical analysis and histopathological classification were carried out in serial tumour samples. RESULTS: The activity of ODC was very low in peritumoral non-neoplastic brain tissue (0.9 (SD 0.6) nmol/g/h). It was significantly higher in gliomas and it significantly increased with a higher grade of malignancy (grade I 2.7 (2.8) nmol/g/h, grade II 3.1 (4.0) nmol/g/h, grade III 5.7 (5.6) nmol/g/h, grade IV 10.6 (11.7) nmol/g/h). High enzyme activity was also found in medulloblastomas (25.5 (15.1) nmol/g/h), malignant lymphomas (52.1 (42.1) nmol/g/h), and metastases from carcinoma (14.9 (22.1) nmol/g/h). Lowest values were measured in epidermoid cysts (0.5 (0.2) nmol/g/h), craniopharyngiomas (1.2 (0.9) nmol/g/h), angioblastomas (1.6 (1.7) nmol/g/h), and neurinomas (2.0 (1.8) nmol/g/h). By contrast with ODC activity, polyamine concentrations did not correlate with the grade of malignancy. Correlation of regional biochemical and histomorphological data in rapidly growing neoplasms showed high enzyme activity in solid tumour parts and low activity in necrotic areas. CONCLUSIONS: Novel data relating ODC activation and polyamine concentrations to neuropathology is presented indicating that high ODC activity represents a biochemical marker of malignancy in brain tumours. This information is important for clinical and therapeutic investigations.

Brain Neoplasms↗
PubMed1991

Further study on polyamine compositions in Vibrionaceae.

It has previously been reported that norspermidine, one of the unusual polyamines, is present in Vibrio species. To expand this observation, the cellular polyamine compositions of additional species and strains in the family Vibrionaceae (Vibrio, Photobacterium, Listonella, and Shewanella) as well as Aeromonas species and Plesiomonas shigelloides, which have been proposed to be excluded from Vibrionacea, were determined by using gas-liquid chromatography. Some Vibrio species previously reported were reexamined under the same conditions, and their results are included in this report. Norspermidine was detected as a major triamine in 23 of 24 Vibrio species, all of 4 Listonella species, and 3 of 5 Photobacterium species. Vibrio costicola, Photobacterium fischeri, and Photobacterium phosphoreum contained no norspermidine. Listonella species were indistinguishable from Vibrio species in their polyamine profiles. However, Schewanella putrefaciens ATCC 8071, formerly allocated in the genus Alteromonas, contained no norspermidine, and its polyamine profile was similar to those of four Aeromonas species, in which putrescine was exclusively found. Plesiomonas shigelloides was very similar to Escherichia coli in that putrescine and spermidine were predominant polyamines. Our data indicate that the occurrence of norspermidine may be very helpful as a generic marker in identification and classification of Vibrio and Listonella species. A gas-liquid chromatographic method with a nitrogen-selective detector was presented for rapid and sensitive detection of cellular norspermidine.

Chromatography, Gas↗
PubMed1991

Polyamine distributions in the Falvobacterium-Cytophaga-Sphingobacterium complex.

Homospermidine was found as the major polyamine in one newly described species of Flavobacterium (F. indologenes), in three species of Sphingobacterium (S. mizutae, S. multivorium, and S. spiritivorum), and in 10 species of Cytophaga (C. aquatilis, C. arvensicola, C. heparina, C. hutchinsonii, C. johnsonae, "C. keratolytica," C. lytica, C. marinoflava, C. uliginosa, and "C. xantha"). These bacteria also all contain putrescine and agmatine as minor components. Flavobacterium indologenes and C. johnsonae contain an unusual diamine, 2-hydroxyputrescine, as a major polyamine. The polyamine distributions of four other species originally included in Flavobacterium (F. acidurans, "F. dormitator," "F. tirrenicum," and Halomonas halmophila), whose taxonomic positions are or were uncertain, were different from the group mentioned above. They either contain spermidine as the major polyamine or lack any polyamine. These results suggest that homospermidine can serve as a chemotaxonomic marker to delineate true members of the Flavobacterium-Cytophaga-Sphingobacterium complex.

Bacteria↗
PubMed1994

Polyamine deficiency causes reorganization of F-actin and tropomyosin in IEC-6 cells.

In earlier work we have shown that polyamine-deficient IEC-6 cells lose most of their ability to migrate. In this report we describe the effect of polyamine deficiency on the cytoskeleton of migrating IEC-6 cells. Cells were grown on cover slips for 4 days. One-third of the monolayer was removed, and the remainder was incubated for 6 h. The monolayers were fixed and stained with rhodamine phalloidin for actin filaments and by immunocytochemistry for tropomyosin. In control cells, actin filaments were found as stress fibers traversing the cell, in a thin actin cortex often visible on only one edge of the cell, and in fine fibers extending into the lamellipodia. Tropomyosin was found in the same distribution. A Western blot showed that tropomyosin was present as 35- and 37-kDa isoforms. In polyamine-deficient cells, actin stress fibers were less dense, whereas the actin cortex was greatly increased in density and lamellipodia were less extensive. Tropomyosin distribution was similar and included a 30-kDa isoform not seen previously. In spite of the obvious changes in the distribution of these cytoskeletal proteins, the concentrations of filamentous actin, beta-actin mRNA, and the higher molecular weight tropomyosin isoforms did not change. In all cases the addition of putrescine to polyamine-deficient cells prevented the changes described. We conclude that polyamines are essential for migration in this system because of their effects on the organization of cytoskeletal actin, tropomyosin, and perhaps other proteins as well.

Actins↗
PubMed1995

Gastrin stimulates expression of protooncogene c-myc through a process involving polyamines in IEC-6 cells.

The current study tested the hypothesis that the protooncogene c-myc is involved in the mechanism by which gastrin modulates mucosal cell proliferation. Studies were conducted in the IEC-6 cell line, derived from rat small intestinal crypt cells. Administration of gastrin resulted in the rapid appearance of c-myc mRNA in IEC-6 cells. The increased expression of c-myc began 1 h and peaked 4 h after exposure to gastrin. Maximum increase in c-myc mRNA levels was 7.5-fold the normal value. When cellular protein synthesis was inhibited by addition of cycloheximide, gastrin superinduced c-myc mRNA levels. Gastrin also significantly increased the mRNA levels for ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis, enzyme activity, and intracellular polyamines in IEC-6 cells. Treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, not only completely depleted intracellular polyamines but also significantly prevented the increased expression of c-myc in cells exposed to gastrin. These results show that 1) gastrin stimulates both polyamine biosynthesis and the expression of the c-myc protooncogene, and 2) depletion of intracellular polyamines by DFMO significantly prevented the increased expression of c-myc by gastrin.

Animals↗
PubMed1993

Decreased expression of protooncogenes c-fos, c-myc, and c-jun following polyamine depletion in IEC-6 cells.

Direct exposure of small intestinal mucosal cells to luminal polyamines stimulates proliferation. This study tests the hypothesis that the protooncogenes c-fos, c-myc, c-jun, and junB are involved in the mechanism by which polyamines modulate mucosal growth. Studies were conducted in the IEC-6 cell line, derived from rat small intestinal crypt cells. Cells were grown in Dulbecco's minimal essential medium containing 5% dialyzed fetal bovine serum (dFBS) in the presence of absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, which is the rate-limiting enzyme for polyamine synthesis. Cellular polyamine levels, cell growth, and relative abundance of c-fos, c-myc, c-jun, and junB mRNAs, were measured at 1, 2, 4, 6, 8, and 12 days after initial plating. The intracellular polyamines, spermidine and spermine, and their precursor, putrescine, in DFMO-treated cells decreased significantly at 2 days and remained depleted thereafter. Although DFMO profoundly decreased growth and final cell number, both control and DFMO-treated cells entered a plateau phase by 6 days. In control cells, c-myc and c-jun mRNA levels significantly increased on days 4-6 and then returned to a basal level of expression, which was maintained thereafter. c-fos mRNA in quiescent cells after 24 h serum deprivation was significantly stimulated by 5% dFBS, although a steady-state level of c-fos mRNA was undetectable in control cells. Treatment with DFMO not only prevented increased expression of c-myc and c-jun protooncogenes at 4 days, but also significantly reduced steady-state levels of c-myc and c-jun mRNA between 6 and 12 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Induction of postprandial intestinal motility and release of cholecystokinin by polyamines in rats.

Polyamines are known to play a major role in postprandial adaptation of the digestive tract. Experiments were designed to determine whether ingested polyamines induce change in intestinal motility associated with a cholecystokinin (CCK) release and whether endogenous polyamines are involved in the intestinal and colonic motor response to a meal. Intestinal and colonic motility was assessed in rats equipped with intestinal electrodes, and plasma CCK was determined using a bioassay. Orogastric administration of putrescine, spermidine, or spermine (20 mumol) disrupted intestinal migrating myoelectric complexes (MMCs) and increased the frequency of colonic spike bursts. After a 6-day treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine, the duration of postprandial disruption of MMCs, but not the stimulation of colonic motility, induced by a 3-g meal was significantly reduced. The duration of MMC disruption and the increase in colonic spike burst frequency after spermidine administration (20 mumol) were significantly reduced by CCK-A and CCK-B antagonists. Eight minutes after saline administration plasma CCK concentration was 0.9 +/- 0.4 pM; it rose to 4.7 +/- 2.8 pM, 8 min after spermidine (20 mumol). These results indicate that exogenous polyamines disrupt intestinal MMCs and stimulate colonic motility through a release of CCK acting at CCK-A and CCK-B receptors and suggest that endogenous polyamines are involved in the postprandial control of intestinal motility.

Animals↗
PubMed1996

Relationship between polyamines, actin distribution, and gastric healing in rats.

Intragastric administration of 3.4 M NaCl damages the gastric mucosa and increases the activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Polyamines are essential for the repair of gastric erosions. Little is known about the restitution of damaged mucosa except that cell migration is essential. Actin is the principal cytoskeletal protein and is essential for migration. This investigation determines the relationship between polyamines, actin, and gastric healing. Rats were fasted for 22 h and given 1.0 ml of 3.4 M NaCl intragastrically and killed 1, 2, 4, 8, and 10 h later. The mucosa was assayed for ODC activity and stained for G- and F-actin. F-actin was concentrated below the damaged mucosa at 1.5, 2, and 4 h. There was no increase in F-actin distribution at any time point, when NaCl-treated animals were given alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC. In addition, DFMO significantly prevented the healing of the mucosal lesions. Spermidine treatment after DFMO + NaCl significantly prevented the effects of DFMO. Cytochalasin D, a potent actin-disrupting drug, significantly delayed normal gastric mucosal healing. The endogenous polyamines increased significantly in NaCl animals. Data indicate that increases in polyamine synthesis after damage influence the distribution of F-actin in vivo, which may play a part in the healing of mucosal erosions.

Actins↗
PubMed1998

Polyamines are required for microtubule formation during gastric mucosal healing.

Polyamines are essential for the repair of gastric and duodenal erosions. Concentrated NaCl (3.4 M) given intragastrically damages the oxyntic gland mucosa and increases the activity of gastric mucosal ornithine decarboxylase (ODC), the first rate-limiting enzyme in polyamine synthesis. The nature of the process of restitution of damaged mucosa is not well known, except that cell migration and the actin cytoskeleton play a prominent role. Microtubules are cytoskeletal components essential for cell migration. The present investigation determines the relationship between polyamines, the distribution of microtubules, and gastric healing in mucosa damaged with hypertonic NaCl solution. Rats were fasted for 22 h and then given 1.0 ml of 3.4 M NaCl intragastrically. Animals were killed 1, 2, 4, 8, and 10 h after 3.4 M NaCl. The oxyntic gland mucosa was removed, and tubulin was visualized by immunofluorescence. Microtubule density was increased around and below the damaged mucosa in the upper one-third of the glandular epithelium at 2 and 4 h and returned to near control levels by 10 h. In rats damaged with 3.4 M NaCl and pretreated intraperitoneally with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, microtubule content was reduced significantly at all time points after NaCl treatment. Addition of spermidine after pretreatment with DFMO and 3.4 M NaCl significantly prevented the effects of DFMO. Colchicine, a potent microtubule-disrupting drug, significantly delayed normal gastric mucosal healing with no effect on ODC activity. These data show that polyamines influence the distribution of microtubules during damage in vivo and indicate a partial mechanism for the dependency of mucosal healing on polyamines.

Animals↗
PubMed1998

A polyamine pathway-mediated mitogenic mechanism in enterochromaffin-like cells of Mastomys.

We have previously demonstrated that in Mastomys species proliferation of gastric enterochromaffin-like (ECL) cells is predominantly regulated by gastrin and by transforming growth factor-alpha (TGF-alpha) in the naive and neoplastic state, respectively. In this study we examined whether these intracellular mitogenic responses are mediated by polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis. An ECL cell preparation of high purity was used to measure the effect of the polyamine derivatives putrescine, spermidine, and spermine on DNA synthesis by bromodeoxyuridine uptake. Both putrescine and spermidine augmented gastrin-stimulated, but not basal, DNA synthesis in naive cells. This proliferative response correlated with an increase in ODC activity that was partially inhibited (20%) by difluoromethylornithine (DFMO), an inhibitor of ODC (IC50, 30 pM). In contrast, all polyamines increased both basal and TGF-alpha-stimulated DNA synthesis as well as ODC activity in tumor ECL cells. DFMO completely inhibited the proliferative response of TGF-alpha (IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this pathway in the regulation of ECL cell transformation.

Animals↗
PubMed1999

Differentiated intestinal epithelial cells exhibit increased migration through polyamines and myosin II.

Early mucosal restitution is a rapid process by which differentiated intestinal epithelial cells migrate to reseal superficial wounds. However, most of the in vitro studies for restitution employ undifferentiated intestinal crypt cells as a model. The transcription factor, Cdx2, plays an important role in the regulation of intestinal epithelial differentiation. Forced expression of the Cdx2 gene in undifferentiated intestinal crypt cells induces the development of a differentiated phenotype. The current study was designed to determine changes in differentiated intestinal epithelial cell migration after wounding in the stable Cdx2-transfected IEC-6 cells and then to examine involvement of polyamines and nonmuscle myosin II in the process of cell motility. Cdx2-transfected IEC-6 cells were associated with a highly differentiated phenotype and exhibited increased cell migration after wounding. Migration of Cdx2-transfected IEC-6 cells were approximately four times that of nontransfected IEC-6 cells. Migration after wounding was associated with significant increases in polyamine synthesis. Depletion of cellular polyamines by 5 mM alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, inhibited cell migration without affecting the differentiated phenotype. DFMO also decreased levels of nonmuscle myosin II mRNA and protein and resulted in reorganization of myosin II, along with a marked reduction in stress fibers. Exogenous spermidine given together with DFMO not only returned nonmuscle myosin II levels and cellular distribution toward normal but also restored cell migration to control levels. These results indicate that 1) Cdx2-transfected IEC-6 cells exhibit increased cell migration after wounding and 2) cellular polyamines are absolutely required for stimulation of cell migration in association with their ability to modulate the structural organization of nonmuscle myosin II.

Animals↗
PubMed2001

Polyamine regulation of ornithine decarboxylase and its antizyme in intestinal epithelial cells.

Ornithine decarboxylase (ODC) is feedback regulated by polyamines. ODC antizyme mediates this process by forming a complex with ODC and enhancing its degradation. It has been reported that polyamines induce ODC antizyme and inhibit ODC activity. Since exogenous polyamines can be converted to each other after they are taken up into cells, we used an inhibitor of S-adenosylmethionine decarboxylase, diethylglyoxal bis(guanylhydrazone) (DEGBG), to block the synthesis of spermidine and spermine from putrescine and investigated the specific roles of individual polyamines in the regulation of ODC in intestinal epithelial crypt (IEC-6) cells. We found that putrescine, spermidine, and spermine inhibited ODC activity stimulated by serum to 85, 46, and 0% of control, respectively, in the presence of DEGBG. ODC activity increased in DEGBG-treated cells, despite high intracellular putrescine levels. Although exogenous spermidine and spermine reduced ODC activity of DEGBG-treated cells close to control levels, spermine was more effective than spermidine. Exogenous putrescine was much less effective in inducing antizyme than spermidine or spermine. High putrescine levels in DEGBG-treated cells did not induce ODC antizyme when intracellular spermidine and spermine levels were low. The decay of ODC activity and reduction of ODC protein levels were not accompanied by induction of antizyme in the presence of DEGBG. Our results indicate that spermine is the most, and putrescine the least, effective polyamine in regulating ODC activity, and upregulation of antizyme is not required for the degradation of ODC protein.

Animals↗
PubMed2006

Polyamine-mediated reduction in human airway epithelial migration in response to wounding is PGE2 dependent through decreases in COX-2 and cPLA2 protein levels.

Both ornithine decarboxylase inhibition to deplete polyamines and cyclooxygenase inhibition diminish the migration response to injury of human airway epithelial cells in tissue culture monolayers by approximately 75%. Restoration of normal migration responses is achieved in the polyamine depleted system either by exogenous reconstitution of polyamines or the addition of prostaglandin E(2) (PGE(2)). However, only PGE(2) was able to restore migration in the cyclooxygenase-inhibited systems. Western blot for cyclooxygenase-2 and cytosolic phospholipase A(2) protein levels and ELISAs for PGE(2) secretion demonstrate dramatic increases over 24-48 h after monolayer wounding. These increases are completely abolished by polyamine depletion or cyclooxygenase inhibition. We conclude that polyamine inhibition decreases cellular migration in response to injury in airway epithelial cells at least in part through inhibiting normal PGE(2) production in response to injury. This may be brought about by decreases in cytosolic phospholipase A(2) and cyclooxygenase-2 protein levels.

Biogenic Polyamines↗
PubMed2005

Potent modulation of intestinal tumorigenesis in Apcmin/+ mice by the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase.

Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc(Min/+) (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3- and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N(1)-acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers.

Acetyltransferases↗
PubMed2002

Effect of hindlimb suspension and clenbuterol treatment on polyamine levels in skeletal muscle.

Polyamines are unbiquitous, naturally occurring small aliphatic, polycationic, endogenous compounds. They are involved in many cellular processes and may serve as secondary or tertiary messengers to hormonal regulation. The relationship of polyamines and skeletal muscle mass of adductor longus, extensor digitorum longus, and gastrocnemius under unloading (hindlimb suspension) conditions was investigated. Unloading significantly affected skeletal muscle polyamine levels in a fiber-type-specific fashion. Under loading conditions, clenbuterol treatment increased all polyamine levels, whereas under unloading conditions, only the spermidine levels were consistently increased. Unloading attenuated the anabolic effects of clenbuterol in predominately slow-twitch muscles (adductor longus), but had little impact on clenbuterol's action as a countermeasure in fast- twitch muscles such as the extensor digitorum longus. Spermidine appeared to be the primary polyamine involved in skeletal muscle atrophy/hypertrophy.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Polyamines in the developing mouse brain.

Polyamine levels were determined during pre- and postnatal development of the male and female mouse brain to assess their possible role during normal brain development. Tissue polyamine levels were increased during periods of neurogenesis and increased cell packing density (assessed by DNA levels) in all brain regions: cerebral cortex, cerebellum, hypothalamus, and rhombencephalon-midbrain. Tissue polyamine levels declined subsequently in a tissue-specific manner toward adult levels. In contrast, the polyamine concentrations per cell were decreased during periods of neurogenesis. A later increase in rhombencephalon-midbrain spermidine levels is consistent with the presumed association of this polyamine with myelin. No sex differences were found in these studies.

Animals↗
PubMed1989

Role of ornithine decarboxylase and polyamines in camostate (Foy-305)-induced pancreatic growth in rats.

This study was designed to investigate changes of ornithine decarboxylase and polyamines during pancreatic adaptation in response to feeding of the synthetic protease inhibitor camostate. alpha-Difluoromethylornithine, an irreversible and specific inhibitor of ornithine decarboxylase, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Cholecystokinin (CCK) plasma levels in camostate-fed rats increased from basal values of 3-4 pmol/l to a maximal level of 27.4 pmol/l after 2h; they then decreased up to 12 h but remained elevated above controls throughout the 30-day experiments. In the camostate group pancreatic ornithine decarboxylase activity was elevated after 2 h, reaching a maximum after 6 h (1,858.5 pmol 14CO2/h/mg DNA, about 200-fold above controls) followed by a significant increase in putrescine after 4 h and spermidine after 24 h while spermine remained unchanged. The trophic parameters increased in the following time sequence: thymidine kinase (12 h), DNA polymerase (12 h), protein (24 h), pancreatic weight (24 h) and DNA (5 days). alpha-Difluoromethylornithine significantly delayed and reduced the camostate-induced increase in ornithine decarboxylase activity and polyamine concentrations as well as the trophic parameters. Application of the CCK receptor antagonist L-364,718 resulted in complete inhibition of the increases in ornithine decarboxylase, polyamines and all trophic parameters. These data indicate an important role for ornithine decarboxylase and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation in rats.

Animals↗
PubMed1990

Polyamines in pancreatic growth.

This chapter reviews available data concerning the role of polyamines in pancreatic growth. Like in many other mammalian cells stimulation of pancreatic proliferation by trophic factors is associated with an early increase in ornithine decarboxylase (ODC) activity with consequent putrescine formation. ODC and putrescine play probably an important role in the initiation but not maintenance of pancreatic growth. The application of the specific ODC inhibitor alpha-difluoromethylornithine (DFMO) alone is not sufficient to judge the role of polyamines in pancreatic growth. For that purpose a combination of substances which inhibit ODC (DFMO) and polyamine oxidase (N1,N4-bisallenylputrescine) and/or S-adenosylmethionine-decarboxylase (SAM-DC) simultaneously has to be investigated. Ideally polyamines from dietary sources and intestinal bacterial flora should be abolished. The uptake of polyamines from the circulation has still to be considered. Studies will be presented proving that though ODC is completely inhibited by DFMO putrescine is still formed via spermidine/spermine N1-acetyltransferase (SAT). The fast increase of ODC in response to growth stimulating factors like cholecystokinin (CCK) is regulated at a pretranslational level by increasing ODC mRNA.

Animals↗