Urinary Polyamines: A Pilot Study on Their Roles as Prostate Cancer Detection Biomarkers.

Current screening methods towards prostate cancer (PCa) are not without limitations. Research work has been on-going to assess if there are other better tests suitable for primary or secondary screening of PCa to supplement the serum prostate specific antigen (PSA) test, which fails to work accurately in a grey zone of 4-10ng/ml. In this pilot study, the potential roles of urinary polyamines as prostate cancer biomarkers were evaluated. PCa, benign prostatic hyperplasia (BPH) patients and healthy controls (HC) showing PSA>4.0ng/ml were enrolled in the study. Their urine samples were obtained, and the urinary levels of putrescine (Put), spermidine (Spd) and spermine (Spm) were determined by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS). Receiver operating characteristics (ROC) curve and Student's t-test were used to evaluate their diagnostic accuracies. Among the three biogenic polyamines, Spm had demonstrated a good diagnostic performance when comparing their levels in PCa patients with BPH patients (1.47 in PCa vs 5.87 in BPH; p<0.0001). Results are in accordance with transrectal ultrasound prostatic biopsy (TRUSPB) results, with an area under curve (AUC) value of 0.83±0.03. Therefore urinary Spm shows potential to serve as a novel PCa diagnostic biomarker, which in turn can help to address the limited sensitivity and specificity problem of serum PSA test.

Hypocaloric diet supplemented with probiotic cheese improves body mass index and blood pressure indices of obese hypertensive patients--a randomized double-blind placebo-controlled pilot study.

BACKGROUND: Gut lactobacilli can affect the metabolic functions of healthy humans. We tested whether a 1500 kcal/d diet supplemented with cheese containing the probiotic Lactobacillus plantarum TENSIA (Deutsche Sammlung für Mikroorganismen, DSM 21380) could reduce some symptoms of metabolic syndrome in Russian adults with obesity and hypertension. METHODS: In this 3-week, randomized, double-blind, placebo-controlled, parallel pilot study, 25 subjects ingested probiotic cheese and 15 ingested control cheese. Fifty grams of each cheese provided 175 kcal of energy. Blood pressure (BP), anthropometric characteristics, markers of liver and kidney function, metabolic indices (plasma glucose, lipids, and cholesterol), and urine polyamines were measured. Counts of fecal lactobacilli and L. plantarum TENSIA were evaluated using molecular methods. The data were analyzed by t-test for independent samples and Spearman's partial correlation analysis. RESULTS: The probiotic L. plantarum TENSIA was present in variable amounts (529.6 ± 232.5 gene copies) in 16/25 (64%) study subjects. Body mass index (BMI) was significantly reduced (p = 0.031) in the probiotic cheese group versus the control cheese group. The changes in BMI were closely associated with the water content of the body (r = 0.570, p = 0.0007) when adjusted for sex and age. Higher values of intestinal lactobacilli after probiotic cheese consumption were associated with higher BMI (r = 0.383, p = 0.0305) and urinary putrescine content (r = 0.475, p = 0.006). In patients simultaneously treated with BP-lowering drugs, similar reductions of BP were observed in both groups. A positive association was detected between TENSIA colonization and the extent of change of morning diastolic BP (r = 0.617, p = 0.0248) and a trend toward lower values of morning systolic BP (r = -0.527, p = 0.0640) at the end of the study after adjusting for BMI, age, and sex. CONCLUSION: In a pilot study of obese hypertensive patients, a hypocaloric diet supplemented with a probiotic cheese helps to reduce BMI and arterial BP values, recognized symptoms of metabolic syndrome.

[Determination and correlation analysis of contents of putrescine, cadaverine, and histamine in necrotic tissue, blood, and urine of patients with diabetic foot].

OBJECTIVE: To determine and perform a correlation analysis of the contents of putrescine, cadaverine, and histamine in necrotic tissue, blood, and urine of patients with diabetic foot (DF). METHODS: Ten patients with severe wet necrotizing DF hospitalized from January 2011 to January 2012 were assigned as group DF, and 10 orthopedic patients with scar but without diabetes or skin ulcer hospitalized in the same period were assigned as control group. Samples of necrotic tissue from feet of patients in group DF and normal tissue from extremities of patients in control group, and samples of blood and 24-hour urine of patients in both groups were collected, and the amount of each sample was 10 mL. Contents of putrescine, cadaverine, and histamine were determined with high performance liquid chromatography-mass spectrometry. The data got from the determination of blood and urine were processed with t test, and those from necrotic or normal tissue with Wilcoxon rank sum test. The correlation of contents of polyamines between necrotic tissue and blood, blood and urine were processed with simple linear regression analysis. RESULTS: (1) Contents of putrescine, cadaverine, and histamine in the necrotic tissue of group DF were (186.1 ± 26.8), (78.553 ± 12.441), (33 ± 10) mg/kg, which were significantly higher than those in normal tissue of control group [(2.2 ± 1.2), (1.168 ± 0.014), 0 mg/kg, with Z values respectively -3.780, -3.781, -4.038, P values all below 0.01]. The content of putrescine in necrotic tissue of group DF was significantly higher than those of cadaverine and histamine (with Z values respectively -3.780, -3.630, P values all below 0.01). (2) Contents of putrescine, cadaverine, and histamine in the blood of group DF were (0.075 ± 0.013), (0.022 ± 0.003), (0.052 ± 0.014) mg/L, and they were significantly higher than those in the blood of control group [(0.014 ± 0.009), (0.013 ± 0.003), (0.016 ± 0.008) mg/L, with t values respectively 6.591, 2.207, 3.568, P < 0.05 or P<0.01]. The content of putrescine in the blood of group DF was significantly higher than those of cadaverine and histamine (with t values respectively 13.204, 3.096, P values all below 0.01). (3) Contents of putrescine, cadaverine, and histamine in the urine of group DF were (0.735 ± 0.088), (0.450 ± 0.012), (0.1623 ± 0.0091) mg/L, and only the contents of putrescine and cadaverine were significantly higher than those in the urine of control group [(0.050 ± 0.014), (0.035 ± 0.007) mg/L, with t values respectively 3.270, 4.705, P<0.05 or P<0.01]. The content of putrescine in the urine of group DF was significantly higher than that of cadaverine (t = 6.686, P < 0.01). (4) There were significant and positive correlations in contents of putrescine, cadaverine, and histamine between necrotic tissue and blood in patients of group DF (with r values respectively 0.981, 0.994, 0.821, P values all below 0.01). There were no significant correlations in contents of putrescine, cadaverine, and histamine between blood and urine in patients of group DF (with r values respectively 0.150, 0.239, 0.177, P values all above 0.05). CONCLUSIONS: Putrescine, cadaverine, and histamine exist in the necrotic tissue of patients with DF in high concentrations, among which putrescine predominates. These polyamines can be absorbed into the blood through wound and excreted through the urine.

Serum and urinary metabonomic study of human osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor found in children. Currently, researchers have focused on protein and gene levels, while the associated metabolic variations have been poorly understood. In this study, we used a gas chromatography mass spectrometry approach and profiled small-molecule metabolites in serum and urine of 24 OS patients, 19 benign bone tumor patients, and 32 healthy controls, to determine whether there are significant alterations associated with carcinogenesis. The metabonomic results demonstrate clear intergroup separations between healthy control subjects and bone tumor patients in the orthogonal partial least-squares-discriminant analysis (OPLS-DA) models. Differential metabolites identified from the metabonomic analysis suggest a disrupted energy metabolism in OS patients, as characterized by significantly down-regulated TCA cycle and glycolysis, down-regulated lipid metabolism, dysregulated sugar levels, and up-regulated amino acid metabolism. Additionally, an increased activity of glutathione metabolism, and increased polyamine metabolism also contributed to a characteristic metabolic signature of OS patients.

Influence of dietary arginine on sexual dimorphism of arginine metabolism in mice.

We have studied the influence of dietary arginine on tissue arginine content, and arginine metabolism in CD1 mice. Dietary arginine restriction produced by feeding mice with a low arginine diet (0.06%) produced a marked decrease in arginine concentrations in the plasma, skeletal muscle and kidney of female mice (72%, 67% and 54%, respectively) while in male mice the decreases were smaller (58% in blood and 18% in the skeletal muscle). This diet abolished not only the sexual dimorphism in arginine content observed in mice fed with the diet containing 1% arginine, but also reduced renal activities of arginase and nitric oxide synthase in the female mice and ornithine decarboxylase and the decarboxylation of arginine in the male mice. Urinary putrescine excretion was dramatically reduced by arginine restriction in the male mice whereas orotic acid excretion increased about 30 fold in both sexes; urea and creatinine excretion did not change. Taken together our results indicate that dietary arginine plays a relevant role in the maintenance of the sexual dimorphism in arginine content and arginine metabolism in CD1 mice, and that this may have physiological significance because of the important effects that arginine-derived products exert on a variety of cellular processes.

Alpha-difluoromethylornithine as treatment for metastatic breast cancer patients.

DFMO (alpha-difluoromethylornithine) is an oral irreversible inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis. DFMO has been shown to have antiproliferative effects against several human cancers, and some studies have suggested that DFMO may have pro-apoptotic and anti-invasive properties as well. DFMO is well tolerated with minimal toxicity but has been associated with ototoxicity with prolonged daily administration. We conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high-dose DFMO in metastatic breast cancer patients. Twenty-one patients were treated with 4800 mg of DFMO p.o. three times a day for 14 days, followed by a 2-week drug holiday on a 28-day cycle. Urinary polyamine and blood DFMO levels were measured at multiple time points during therapy. High-dose DFMO was well tolerated, and no clinically significant ototoxicity was noted. No patient achieved an objective antitumor response; however, one patient with heavily pretreated liver metastases has achieved stable disease for 18 months to date on DFMO. Putrescine, spermine, and spermidine urinary levels were suppressed with DFMO treatment and remained low during the 2-week drug holiday. High-dose DFMO on a schedule of 2 weeks on treatment followed by 2 weeks off is well tolerated, is not associated with ototoxicity, and leads to sustained suppression of urinary polyamine levels. Although not an active cytotoxic agent for metastatic breast cancer, the intriguing prolonged growth arrest of liver metastases in one patient highlights the potential clinical growth inhibitory properties of DFMO. We believe that DFMO is worthy of study as adjuvant therapy in primary breast cancer patients and as a chemopreventive agent.

Dietary induction of ornithine decarboxylase in male mouse kidney.

In male mouse kidney, ornithine decarboxylase (ODC) is induced after feeding, and the induction depends on dietary protein content. 24 h after feeding with 50% casein-containing meal, ODC activity and amount of immunoreactive ODC protein increased more than 10-fold, ODC mRNA level increased 2-fold, and the ODC half-life extended 7-fold. The renal ODC induction after feeding is, therefore, due mainly to stabilization of ODC protein. Urinary excretion of putrescine increased in response to the ODC induction, but the renal polyamine contents scarcely changed. Consistently, the level of antizyme, a polyamine-inducible protein, determined as the ODC-antizyme complex level, scarcely changed after feeding, and the antizyme/ODC ratio in the kidney largely decreased, resulting in the stabilization of ODC protein. The present results suggest that the strong excretion system of the kidney for newly synthesized polyamines enables renal ODC escape from antizyme-mediated feedback regulation.

Postnatal exposure to androgens alters renal ornithine decarboxylase ontogeny and abolishes renal sexual dimorphism in mice.

The mouse kidney presents marked sexual dimorphism, manifested not only in renal size but also in the subcellular structure and enzyme activity. Ornithine decarboxylase (ODC), a key enzyme in the biosynthetic pathway of polyamines, is induced in the kidney by androgens, and its activity is higher in the kidney of male mice. The renal differences between male and female mice are not manifested during the first weeks of life and start to be expressed after weaning, simultaneously with the increase in plasma testosterone concentration. Treatment of newborn mice before postnatal day 21 with a single dose of testosterone propionate (TP, 200 microg/animal) did not increase renal ODC activity or renal size. From day 21 the same treatment elicited significant increases in renal ODC, especially in females where the basal activity of control animals was much lower than in males. The repeated injection of TP during the first 10 days of life (200 microg/animal, days 1, 4, 7 and 10) promoted an early increase in renal ODC activity but abolished the physiological rise observed in male mice at puberty and adulthood. This treatment dramatically reduced the secretion of the sexual hormones, testosterone, estradiol and progesterone, by the gonads, and diminished renal size as well as ODC and beta-glucuronidase activities in male mice. Stanozolol produced effects similar to those of TP, while the nonsteroidal antiandrogen, flutamide, did not apparently affect the normal development of the male or female kidney. The results indicate that: (a) kidney sexual dimorphism is not congenital; (b) neonatal androgens are not required to induce the sexual dimorphism of the mouse kidney; (c) the neonatal kidney is unresponsive to testosterone; (d) the premature and repeated exposure to supraphysiological levels of testosterone may accelerate the ontogeny of renal ODC but can abolish later testosterone secretion and hence alter the sexual characteristics of the male kidney, and (e) the postnatal treatment with androgens does not affect the response of the adult kidney to exogenous androgens. One can conclude that the postnatal manipulation of androgens may accelerate the development of the mechanisms of androgen responsiveness in some tissues but it may alter neural structures, probably the GnRH pulse generator, that control testosterone secretion.

Urinary excretion of polyamines in the adult respiratory distress syndrome.

Polyamines are low molecular weight polycations that are critically important in cellular proliferation and differentiation. To investigate their potential role in acute lung injury, the polyamines spermidine, spermine, and putrescine were measured in 24-h urine collections from intubated patients with ARDS (n = 12) or congestive heart failure with cardiogenic pulmonary edema (CHF, n = 10) and in normal subjects (n = 10). Mean concentrations of putrescine were similar between groups, but spermidine concentrations in patients with ARDS (52.7 +/- 19.7 nmol/mg creatinine) were significantly higher than in normal subjects (4.9 +/- 0.7 nmol/mg), p < .05. Mean concentrations of spermine in ARDS (270.6 +/- 78.1 nmol/mg) were higher than in CHF (1.0 +/- 0.5 nmol/mg), p < .05, and normal subjects (0.3 +/- 0.1 nmol/mg), p < .05. Concentrations of putrescine increased significantly during the first 7 days of ARDS (241.5 +/- 127.1% above baseline, n = 6), p < .05. Urinary polyamine excretion did not correlate with severity of gas exchange or death. These results are the first to suggest a potential role for polyamines in the pathophysiology of ARDS.

Influence of diet with or without amino acids on polyamine excretion in multiple trauma victims.

Elevated levels of urinary polyamines (PA) in severely injured trauma patients are further enhanced by total parenteral nutrition (TPN) that contains both glucose and amino acids (AAs). Since TPN solutions contain arginine, the AA precursor of PA, it is not certain whether the increased urinary PA are due to this substrate. Nutritional factors can evidently modify PA metabolism. We measured the daily excretion of the PA, putrescine (PU) and spermidine (SD) in 18 multiply injured (injury severity score [ISS], 32 +/- 2), hypermetabolic (resting energy expenditure [REE]/basal energy expenditure [BEE], 1.41 +/- 0.06), and highly catabolic (daily N loss, 17.2 +/- 1.8 g N/d) acute trauma patients for 5 days in the early flow phase of injury. The patients were fed only maintenance fluids without calories or nitrogen for the first day 60 to 72 hours after injury, and then were randomized to receive glucose alone ([GLUC] 4.1 mg/kg/min, 80% measured REE, n = 8) or the same amount of glucose with AAs (TPN, 275 mg N/kg/d, n = 10) for the following 4 days. There was no significant difference in the enhanced daily PA excretion either in the free or acetylated form between the two dietary regimens. The addition of AAs in the TPN mixture did not seem to further stimulate PA metabolism in the trauma patients. The source of the nutrient content of the diet appears to be important for enhancing total PA excretion in critically ill patients.

An improved method of determining free and acetylated polyamines by HPLC involving an enzyme reactor and an electrochemical detector.

We developed an improved system for the simultaneous measurement of free and acetylated polyamines, which comprised a HPLC pump, a separation column, an enzyme reactor, and an electrochemical detector, connected in series. Polyamines were separated with an isocratic elution system, and the separated polyamines were introduced into the enzyme reactor, in which they were deacetylated and oxidized to generate hydrogen peroxide. The amount of hydrogen peroxide generated was then determined with the electrochemical detector. Analysis of a mixture of nine standard polyamines including both free forms and acetylated derivatives with this method revealed that the analytical variables were satisfactory. For the analysis of polyamines in urine, pretreatment of samples with a weakly acidic ion exchange resin was necessary to reduce the interfering substances present in the urine. On successive determinations of polyamines in a urine sample, the coefficients of variation obtained were below 5.4%, except that for spermine (27.6%), and the analytical recovery rates were above 90%, except that for acetylputrescine (78.5%). The correlation coefficient between the total polyamine content in urine estimated by our method and that obtained by means of a commercially available enzymatic assay system was calculated to be 0.98, and the regression equation was expressed as y = 0.81 x + 0.89.

Whole body energy expenditure protein breakdown and polyamine excretion during high dose treatment with interleukin-2 and interferon-alpha.

OBJECTIVE: To correlate changes in whole body resting energy expenditure and protein breakdown with the production of stress hormones, excretion of polyamines, and circulating concentrations of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), in patients undergoing treatment with high doses of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). DESIGN: Prospective open study. SETTING: University Department of Surgery. SUBJECTS: 11 Patients with malignant melanoma (n = 8) or renal cell carcinoma (n = 3) all of whom had a Karnofsky score of 80 or more. INTERVENTIONS: Daily intravenous infusion of IL-2 (18 x 10(6) IU/m2/day) and subcutaneous injection of IFN-alpha (3 x 10(6) IU/m2/day) for days 1-5 and 8-12 in two courses with a three week interval. MAIN OUTCOME MEASURES: Energy expenditure measured by indirect calorimetry, body temperature, heart rate, urinary excretion of amino acids and nitrogen, and plasma cytokine concentrations. RESULTS: Three patients had a partial response. IL-1 was not detectable in plasma; and concentrations of IL-2 increased rapidly during the infusion before falling rapidly when it stopped, of IL-6 increased significantly (mean (SEM) 3.44 (1.6) to 11 (2) U/ml, p < 0.05), and of TNF-alpha increased by 295% (p < 0.05). Resting energy expenditure increased from 92 (4) to 113 (4) kJ/kg/day (p < 0.001) during the infusion and this was accompanied by a rise in temperature and an increase in the urinary excretion of cortisol (which also correlated with increased breakdown of whole body protein). CONCLUSION: The increased energy expenditure and protein breakdown were probably a result of stimulation of production of catecholamines and cortisol, as after injury, but the direct effects on temperature regulating neurons may be important.

Postnatal development of ornithine decarboxylase and polyamines in the mouse kidney: influence of testosterone.

The role of ornithine decarboxylase (ODC) and polyamines in kidney growth during the postnatal development of mice and the influence of testosterone were investigated. A marked sexual dimorphism in renal size was evident after the 3rd week of life, corresponding with the rise in circulating testosterone and the increase in renal ODC and urinary excretion of putrescine in male mice. Renal putrescine and spermidine gradually decreased during the first 3 weeks of life and did not correlate with ODC activity. Treatments with alpha-difluoromethylornithine, and ODC-specific inhibitor, and the antiandrogen flutamide during weeks 4 and 5 showed that both compounds decreased renal ODC activity but only flutamide impaired kidney growth, suggesting that renal growth in mice is regulated by androgens but is independent of the induction of ODC activity.

[Urinary excretion of acetylated polyamines after heart transplantation in dogs]. / L'excrétion urinaire des polyamines acétylés après la transplantation cardiaque chez le chien.

Increase in urinary polyamine levels after transplantation was suggested to be an indicator of organ rejection but immunosuppression therapy could also give rise to these polyamines. To test this hypothesis, the urinary excretion of N-acetylputrescine (Nap) and N-acetylspermidine (Nas) was studied in 36 dogs. Two groups (n = 6) underwent cervical heterotopic heart transplantation. Three other groups (n = 6) were given different immunosuppression treatments without having any surgery and one group (n = 6) had a sham cervical operation. Urine samples and percutaneous transmural biopsy of the transplanted heart were collected daily. The acetylated polyamines were measured with high performance liquid chromatography (HPLC). Immunosuppression of the transplanted dogs with cyclosporine, imuran and prednisone during the postoperative period caused a significant increase (p < 0.05) in the excretion of Nas averaging 512 +/- 122, 929 +/- 337, 507 +/- 207, 1008 +/- 665, 674 +/- 273 nmol/mg of creatinine respectively compared to 197 +/- 31, 149 +/- 30, 203 +/- 56, 177 +/- 40, 226 +/- 62 nmol/mg of creatinine. The excreted levels of Nap for the same group were 594 +/- 202, 707 +/- 138, 1007 +/- 270, 1055 +/- 358, 827 +/- 270 nmol/mg of creatinine compared to 71 +/- 24, 169 +/- 36, 150 +/- 23, 136 +/- 29, 197 +/- 32 nmol/mg of creatinine (p < 0.05) in the control group of sham operated animals. A significant excretion of Nas and Nap was also observed between the transplanted dogs under immunosuppression and the immunosuppressed but non-operated animals, as well as with the non-operated animals that were given cyclosporine only.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of sepsis and trauma on urinary excretion of polyamines.

Urinary excretion of polyamines increases in patients with trauma and infection. To separate the effect of infection from the general metabolic response to sepsis, we studied 7 patients with sepsis and 13 patients with multiple trauma in the intensive-care unit. Urinary excretion of total and free polyamines, putrescine, spermidine, spermine, and their metabolites N1-acetylspermidine (N1-AcSPD) and N8-acetylspermidine (N8-AcSPD), and energy and nitrogen balance were measured. The patients were randomized to receive either hypocaloric glucose alone or with amino acids for 2 days. The excretion of individual polyamines, except spermine, significantly exceeded normal values in both patient groups; the excretion of total polyamines was 530 and 323% higher than normal in patients with sepsis and trauma, respectively. The excretion of N1-AcSPD and total spermidine was 141 and 74% higher in patients with sepsis than in patients with trauma, respectively (p < 0.05), whereas the excretion of N8-AcSPD was equal in both patient groups. This was also reflected as a significantly increased urinary ratio of N1-AcSPD to N8-AcSPD in septic patients (6.37 +/- 1.61; mean +/- SE) compared with patients after injury (2.69 +/- 0.27, p < 0.01) or a healthy population (1.08 +/- 0.04, p < 0.001). Amino acid infusion had no effect on polyamine excretion. The mean energy balance was -17.0 +/- 1.1 and -19.1 +/- 1.1 kcal.kg-1.day-1, and the mean nitrogen balance was -0.17 +/- 0.03 and -0.15 +/- 0.02 g.kg-1.day-1 in patients with sepsis and trauma, respectively (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary and erythrocyte polyamines during the evaluation of oral alpha-difluoromethylornithine in a phase I chemoprevention clinical trial.

Pharmacokinetics of alpha-difluoromethylornithine (DFMO) in plasma and polyamine levels in urine and erythrocytes (RBC) of subjects considered to be at a higher-than-normal risk for developing cancer and receiving DFMO in a phase I chemoprevention trial were monitored over a period of 6 months at DFMO doses ranging from 200 to 6400 mg/m2/day. DFMO pharmacokinetics was linear and attained an average peak plasma concentration of 58 micrograms/ml and an average area under the concentration x time curve from 0 to 6 h of 240 micrograms/ml.h at an administered dose of 1600 mg/m2. Transient decreases in RBC polyamine levels were observed in only 3 of 22 subjects; all of the others showed an increase in the levels at some time during DFMO administration. In contrast to these findings, 17 of 22 subjects showed a decline in urinary polyamines; 10 of 22 showed this decline by the end of the first month and the remaining subjects during subsequent administration of the drug. One subject with familial polyposis who had high RBC and urinary polyamine levels prior to DFMO treatment showed a significant decline in urinary polyamines and responded to DFMO treatment with nearly complete resolution of the polyps in the rectal stump. Our results suggest that (a) DFMO concentrations achieved in this study are adequate to modulate polyamine pools as reflected by their reduced urinary excretion; (b) the red blood cell polyamines are not reliable indicators of DFMO activity; and (c) the modulation of polyamines occurs at doses of DFMO that are tolerated by a majority of the subjects.

Altered tissue polyamine levels due to ornithine-alpha-ketoglutarate in traumatized growing rats.

All cells contain significant amounts of polyamines (PA), and their concentrations are highly regulated. Metabolic activity within a tissue may be reflected in the amount of intracellular PA. Since trauma involves accelerated death and regeneration of tissues, the related levels of PA in extracellular and intracellular fluids may reflect altered protein metabolism. Trauma induces an increased excretion of urinary PA, and the tissues responsible for this whole-body activity are not known. During posttraumatic nutritional management, supplementation with ornithine-alpha-ketoglutarate (OKG) seems to improve nitrogen economy. The present study evaluates the significance of muscle, liver, and intestine PA responses in traumatized (bilateral femur fractures) rats to the feeding of an isonitrogenous liquid diet supplemented with or without OKG. Uninjured control rats were pair-fed with respective traumatized rats. After 2 days of starvation and 4 days of feeding, the traumatized and control rats were killed and the tissues were excised and analyzed. Starvation decreases and refeeding increases urinary PA excretion. Trauma-induced PA response is predominantly seen in muscle tissues, and this may be responsible for parallel increases in PA excretion. Liver PA responses show a varying tendency confirming the increased protein synthetic activity due to trauma. Intestine has the highest intracellular PA levels, and there is a general smaller (statistically insignificant) increase in all the individual PA contents due to trauma. OKG supplementation augments tissue and urine PA responses in control rats; however, in trauma rats muscle PA levels show very little change, although nitrogen retention is significantly better (88% to 77%). Mechanistic studies are needed to evaluate the significances of the time-dependent, injury-induced, individual intracellular PA levels.

Urinary polyamines in patients with advanced cervical cancer or pelvic cancer recurrence during and after radiotherapy.

The urinary excretion of polyamines was evaluated before, during and after radiotherapy in 16 patients with advanced squamous cell carcinoma of the uterine cervix (stage IIb or IIIb) and in 7 cases with pelvic recurrence after surgery for various types of carcinoma. The concentration of spermidine was significantly higher in the patients with primary tumors than in those with recurrent tumors. After the first radiation fractions putrescine increased in the patients with primary tumors whereas it decreased in patients with recurrent tumors. The values tended to return to baseline levels with time following treatment initiation. Polyamine increased markedly during treatment in patients who remained disease-free for at least 5 years but not in the patients with progressive disease or relapse. The results suggest a different polyamine metabolism and a different response to radiotherapy of recurrent tumors compared to primary tumors. The increase of urinary polyamines, but not the baseline values, seemed to be correlated to the response after radiotherapy.

[Raised polyamines in erythrocytes of DMH administrated rats with colonic cancers and those relationship to tumor volume].

The objective of this study was to assess, in a controlled experimental system, whether the concentrations of polyamines (Pa) in urine or erythrocytes increase during the process of colon carcinogenesis in rats, and whether such changes reflect tumor volume. Colon carcinoma was induced in Sprague-Dawley rats by subcutaneous injection of 1, -2 dimethylhydrazine (DMH). 24-hour urine and blood samples were collected and analysed for their Pa consent, with high pressure liquid chromatographic method. The levels of any Pa derivatives in either urine or erythrocytes at 32 weeks after the administration of DMH were not significantly high compared with the control group at the same week. However, certain increases of Pa in erythrocytes were observed in the levels of putrescine (1.3 times), spermidine (1.3 times), and spermine (1.5 times) respectively compared with the control group and there were high positive correlations between tumor volume and the levels of each Pa derivatives. On the ground of the results, Pa in erythrocytes seems to be the sensitive parameter for tumor volume compared with Pa in urine.