High Ornithine Decarboxylase Activity Research Articles

High expression of antizyme inhibitor 2, an activator of ornithine decarboxylase in steroidogenic cells of human gonads

High activity of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine synthesis, is typically present in rapidly proliferating normal and malignant cells. The mitotically inactive steroidogenic cells in rodent testis and ovaries, however, also display high ODC activity. The activity of ODC in these cells responds to luteinizing hormone, and inhibition of ODC reduces the production of steroid hormones. Polyamines and ODC also control proliferation of germ cells and spermiogenesis. The activity of ODC, especially in proliferating cells, is regulated by antizyme inhibitor (AZIN). This protein displaces ODC from a complex with its inhibitor, antizyme. We have previously identified and cloned a second AZIN, i.e. antizyme inhibitor 2 (AZIN2), which has the highest levels of expression in brain and in testis. In the present study, we have used immunohistochemistry and in situ hybridization to localize the expression of AZIN2 in human gonads. We found a robust expression of AZIN2 in steroidogenic cells: testicular Leydig cells and Leydig cell tumors, in ovarian luteinized cells lining corpus luteum cysts, and in hilus cells. The results suggest that AZIN2 is not primarily involved in regulating the proliferation of the germinal epithelium, indicating a different role for AZIN1 and AZIN2 in the regulation of ODC. The localization of AZIN2 implies possible involvement in the gonadal synthesis and/or release of steroid hormones.

Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells

Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in cell cycle, tumor promotion and anti-apoptosis. In our previous studies, overexpression of ODC prevented apoptosis induced by tumor necrosis factor-α and methotrexate. We further investigated the apoptotic mechanisms of the cancer chemotherapeutic drugs, including etoposide (VP-16), paclitaxel (TAX) and cisplatin (CDDP), and the influences of ODC on apoptosis and cell cycle. Our results showed that the investigated drugs induced caspase-dependent apoptosis, the generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (Δ ψ m) in HL-60 cells, all of which were reversed by putrescine, glutathione or N-acetyl- l-cysteine. Overexpression of ODC prevented the cancer chemotherapeutic drugs-induced apoptosis, ROS generation and the disruption of Δ ψ m. After drug administrations, the decline of Bcl-2, cytochrome c release and caspases’ activation were inhibited by ODC overexpression. In cell cycle, ODC overexpressed cells seemed to overcome the G1 arrest and G2/M arrest, caused by VP-16 and TAX, respectively, and kept on the cell cycle rolling. Overexpression of ODC increased the expression of Cyclin A, D, E and Cdk4 and the enzyme activity of Cdk1 and Cdk2 after the treatment of VP-16 and TAX, respectively. In conclusions, the cancer chemotherapeutic drugs-induced apoptosis is through ROS-related, mitochondria-mediated and caspase-dependent pathways. With higher ODC activity, cells are resistant to the cancer chemotherapeutic drugs-induced apoptosis and keep on the cell cycle rolling with the significant interference in G1/S arrest caused by VP-16 and G2/M arrest by TAX.

ORNITHINE DECARBOXYLASE ACTIVITY AS A PROGNOSTIC MARKER FOR COLORECTAL CANCER

Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines, which are essential for cell proliferation. ODC activity was measured in 47 colorectal cancer patients, 5 patients with adenoma of colorectum and 4 healthy volunteers. Mean ODC activities of cancer tissue, non-cancerous mucosa from cancer-bearing colorectum, adenoma tissue, and normal mucosa from healthy volunteers were 435+/-392, 154+/-173, 295+/-202, 103+/-60 pmol CO2/h/mg protein, respectively. ODC activity of cancer tissue or adenoma tissue was significantly higher than that of the others. Among colorectal cancer patients, ODC activity in cancer tissue was correlated with T factors, lymph node metastasis and stages. Patients with tumors that had high ODC activity (> or =350 pmol CO2/h/mg protein) showed a poor 10-year survival rate. These results suggest that ODC activity may be a useful marker for patients' prognosis after surgery.

Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors

Inhibitors of histone deacetylases (HDAC) show significant promise as targeted anticancer agents against a variety of hematologic and solid tumors. HDAC inhibitors arrest the growth of primary cells, but they induce apoptosis or differentiation of tumor cells. Although the precise mechanism is unknown, differences in cell cycle checkpoints and chromatin structure may be responsible. Cellular polyamines regulate both cell cycle progression and chromatin structure. In tumors, polyamines are abundantly produced because of increased activity of the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC). To determine if polyamines contribute to the cellular response to HDAC inhibitors, we inhibited ODC activity with alpha-difluoromethylornithine. Polyamine depletion increased resistance to apoptosis induced by HDAC inhibitors. In addition, we found that ODC activity levels correlated with sensitivity to HDAC inhibitors in a panel of tumor cell lines. We conclude that polyamines participate in the cellular response to HDAC inhibitors and that ODC activity correlates with sensitivity to HDAC inhibitor-induced apoptosis. Thus, elevated polyamine levels might be a biomarker for tumor sensitivity to HDAC inhibitor-induced apoptosis. These findings warrant clinical evaluation of tumor samples to determine if high ODC activity levels predict sensitivity to HDAC inhibitors.

Changes in ornithine decarboxylase activity in response to temperature stress and stimulation of juvenile hormone in Anastrepha fraterculus (Diptera, Tephritidae)

Ornithine decarboxylase (ODC) activity was analyzed in Anastrepha fraterculus (Diptera) females (4 days old) submitted to temperature stress (6 degrees C and 20/6 degrees C) and the topical application of juvenile hormone (JH). ODC activity and ejaculatory apodeme measurements (length and width) were made in males (15 days old) after 6 degrees C stress. JH dose of 500 ng and incubation of 3, 7, and 18 h increased ODC activity. Females reared at 6 degrees C and 20/6 degrees C had higher ODC activity than those reared at 25 degrees C. The treatment of 6 degrees C and JH incubation for 1 h increased ODC activity when compared to 6 degrees C treatments only. However, the treatment of 20/6 degrees C only after 3 or 18 h of JH incubation resulted in higher ODC activity than controls (20/6 degrees C) or 20/6 degrees C plus 1 h of JH incubation. Males did not undergo differences in ODC activity when reared at 6 degrees C or 25 degrees C but the ejaculatory apodeme measurements was higher in those reared at 25 degrees C than in those reared at 6 degrees C. The results can be considered an adaptive process to environmental changes.

Concurrent overexpression of ornithine decarboxylase and spermidine/spermine N1-acetyltransferase further accelerates the catabolism of hepatic polyamines in transgenic mice

We have generated a hybrid transgenic mouse line overexpressing both ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT) under the control of the mouse metallothionein (MT) I promoter. In comparison with singly transgenic animals overexpressing SSAT, the doubly transgenic mice unexpectedly displayed much more striking signs of activated polyamine catabolism, as exemplified by a massive putrescine accumulation and an extreme reduction of hepatic spermidine and spermine pools. Interestingly, the profound depletion of the higher polyamines in the hybrid animals occurred in the presence of strikingly high ODC activity and tremendous putrescine accumulation. Polyamine catabolism in the doubly transgenic mice could be enhanced further by administration of zinc or the polyamine analogue N1,N11-diethylnorspermine. In tracer experiments with [14C]spermidine we found that, in comparison with syngenic animals, both MT-ODC and MT-SSAT mice possessed an enhanced efflux mechanism for hepatic spermidine. In the MT-ODC animals this mechanism apparently operated in the absence of measurable SSAT activity. In the hybrid animals, spermidine efflux was stimulated further in comparison with the singly transgenic animals. In spite of a dramatic accumulation of putrescine and a profound reduction of the spermidine and spermine pools, only marginal changes were seen in the level of ODC antizyme. Even though the hybrid animals showed no liver or other organ-specific overt toxicity, except an early and permanent loss of hair, their life span was greatly reduced. These results can be understood from the perspective that catabolism is the overriding regulatory mechanism in the metabolism of the polyamines and that, even under conditions of severe depletion of spermidine and spermine, extremely high tissue pools of putrescine are not driven further to replenish the pools of the higher polyamines.

Concurrent overexpression of ornithine decarboxylase and spermidine/spermine N(1)-acetyltransferase further accelerates the catabolism of hepatic polyamines in transgenic mice.

We have generated a hybrid transgenic mouse line overexpressing both ornithine decarboxylase (ODC) and spermidine/spermine N(1)-acetyltransferase (SSAT) under the control of the mouse metallothionein (MT) I promoter. In comparison with singly transgenic animals overexpressing SSAT, the doubly transgenic mice unexpectedly displayed much more striking signs of activated polyamine catabolism, as exemplified by a massive putrescine accumulation and an extreme reduction of hepatic spermidine and spermine pools. Interestingly, the profound depletion of the higher polyamines in the hybrid animals occurred in the presence of strikingly high ODC activity and tremendous putrescine accumulation. Polyamine catabolism in the doubly transgenic mice could be enhanced further by administration of zinc or the polyamine analogue N(1),N(11)-diethylnorspermine. In tracer experiments with [(14)C]spermidine we found that, in comparison with syngenic animals, both MT-ODC and MT-SSAT mice possessed an enhanced efflux mechanism for hepatic spermidine. In the MT-ODC animals this mechanism apparently operated in the absence of measurable SSAT activity. In the hybrid animals, spermidine efflux was stimulated further in comparison with the singly transgenic animals. In spite of a dramatic accumulation of putrescine and a profound reduction of the spermidine and spermine pools, only marginal changes were seen in the level of ODC antizyme. Even though the hybrid animals showed no liver or other organ-specific overt toxicity, except an early and permanent loss of hair, their life span was greatly reduced. These results can be understood from the perspective that catabolism is the overriding regulatory mechanism in the metabolism of the polyamines and that, even under conditions of severe depletion of spermidine and spermine, extremely high tissue pools of putrescine are not driven further to replenish the pools of the higher polyamines.

Targeted overexpression of ornithine decarboxylase enhances β-adrenergic agonist-induced cardiac hypertrophy

These studies were designed to determine the consequences of constitutive overexpression of ornithine decarboxylase (ODC) in the heart. Induction of ODC is known to occur in response to agents that induce cardiac hypertrophy. However, it is not known whether high ODC levels are sufficient for the development of a hypertrophic phenotype. Transgenic mice were generated with cardiac-specific expression of a stable ODC protein using the α-myosin heavy-chain promoter. Founder lines with > 1000-fold overexpression of ODC in the heart were established, resulting in a 50-fold overaccumulation of putrescine, 4-fold elevation in spermidine, a slight increase in spermine and accumulation of large amounts of cadaverine compared with littermate controls. Despite these significant alterations in polyamines, myocardial hypertrophy, as measured by ratio of heart to body weight, did not develop, although atrial natriuretic factor RNA was slightly elevated in transgenic ventricles. However, stimulation of β-adrenergic signalling by isoproterenol resulted in severe hypertrophy and even death in ODC-overexpressing mice without further altering polyamine levels, compared with only a mild hypertrophy in littermates. When β1-adrenergic stimulation was blocked by simultaneous treatment with isoproterenol and the β1 antagonist atenolol, a significant, although reduced, hypertrophy was still present in the hearts of transgenic mice, suggesting that both β1 and β2 adrenergic receptors contribute to the hypertrophic phenotype. Therefore these mice provide a model to study the in vivo co-operativity between high ODC activity and activation of other pathways leading to hypertrophy in the heart.

Targeted overexpression of ornithine decarboxylase enhances beta-adrenergic agonist-induced cardiac hypertrophy.

These studies were designed to determine the consequences of constitutive overexpression of ornithine decarboxylase (ODC) in the heart. Induction of ODC is known to occur in response to agents that induce cardiac hypertrophy. However, it is not known whether high ODC levels are sufficient for the development of a hypertrophic phenotype. Transgenic mice were generated with cardiac-specific expression of a stable ODC protein using the alpha-myosin heavy-chain promoter. Founder lines with >1000-fold overexpression of ODC in the heart were established, resulting in a 50-fold overaccumulation of putrescine, 4-fold elevation in spermidine, a slight increase in spermine and accumulation of large amounts of cadaverine compared with littermate controls. Despite these significant alterations in polyamines, myocardial hypertrophy, as measured by ratio of heart to body weight, did not develop, although atrial natriuretic factor RNA was slightly elevated in transgenic ventricles. However, stimulation of beta-adrenergic signalling by isoproterenol resulted in severe hypertrophy and even death in ODC-overexpressing mice without further altering polyamine levels, compared with only a mild hypertrophy in littermates. When beta1-adrenergic stimulation was blocked by simultaneous treatment with isoproterenol and the beta1 antagonist atenolol, a significant, although reduced, hypertrophy was still present in the hearts of transgenic mice, suggesting that both beta1 and beta2 adrenergic receptors contribute to the hypertrophic phenotype. Therefore these mice provide a model to study the in vivo co-operativity between high ODC activity and activation of other pathways leading to hypertrophy in the heart.

Polyamine metabolism in brain tumours: diagnostic relevance of quantitative biochemistry

OBJECTIVEActivation 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...

Preoperative values of CA 15-3 and CEA as prognostic factors in breast cancer: a multivariate analysis.

The role of circulating tumor markers in providing prognostic information has not been widely studied. In the current study, serum levels of the carbohydrate antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) were determined preoperatively in 364 breast cancer patients with no clinical signs of metastasis. The prognostic relevance of these markers for recurrence (175/364) and death of disease (104/175) was determined by Cox multivariate analysis, including the comparison with classical prognostic factors. High levels of both tumor markers were associated with aneuploid tumors with high S-phase fraction and high ornithine decarboxylase activity. CA 15-3 was highly associated with the number of positive lymph nodes and peritumoral lymphatic or blood vessel invasion. No significant associations were found between CEA or CA 15-3 levels and histologic grade, necrosis and steroid receptor status. In univariate analysis, preoperative values, using optimum cutoff values of CA 15-3 (40 U/ml) and CEA (6 ng/ml), were statistically significant for relapse-free survival and overall survival. In multivariate analysis, only node status, DNA ploidy and ornithine decarboxylase activity were independent predictors for relapse-free survival; the estrogen receptor status was a predictor of overall survival. In node-negative patients, ornithine decarboxylase activity was the only factor selected for relapse-free survival. In node-positive patients, the number of lymph nodes and DNA ploidy were the only variables selected for relapse-free survival or overall survival. Estrogen receptor and ornithine decarboxylase activity were excluded for relapse-free survival, but were significant prognostic factors for overall survival.

Increased colonic ornithine decarboxylase activity in inflammatory bowel disease in children.

The risk of colorectal carcinoma is increased in pediatric-onset inflammatory bowel disease (IBD). There is little information available regarding the colonic mucosal proliferative state in children with IBD. The aim of this study was to assess colonic ornithine decarboxylase (ODC) activity, a marker of cell proliferation, in pediatric IBD patients. ODC activity was assessed in colonic mucosa from 23 children (7 with ulcerative colitis, 9 with Crohn's disease, and 7 controls) undergoing colonoscopic examination. ODC activities were then compared with degree of inflammation of biopsied samples. ODC activities in patients with and without corticosteroid treatment were also analyzed. The mucosal ODC activities of sigmoid colon and rectum were significantly higher (2.5- to 4-fold) in both ulcerative colitis and Crohn's disease. The higher ODC activity was associated with increased mucosal inflammation. Moreover, treatment with corticosteroids decreased the ODC activity. In conclusion, using ODC activities as a marker of cell proliferation, our results suggest that there is a higher colonic mucosal proliferative state in children with IBD. The increased ODC activities were associated with increased colonic mucosal inflammation. Colonic mucosal ODC activity may provide an additional parameter to access the therapeutic efficacy of corticosteroid treatment in pediatric IBD patients.

Effects of 50 Hz magnetic fields on UV-induced skin tumourigenesis in ODC-transgenic and non-transgenic mice

. Purpose: To study the possible role of 50 Hz magnetic fields (MF) in UV-induced skin tumourigenesis using a sensitive animal model. Materials and methods: Transgenic mice (line K2) over-expressing the human ornithine decarboxylase (ODC) gene and their nontransgenic littermates were exposed for 10.5 months to UV-only or a combination of UV and a continuous (100 mu T) or an intermittent MF with varying intensity (1.3-130 mu T). Results: Both MF exposure and transgenicity enhanced the onset rate of macroscopically detectable tumours, but the effect was statistically significant only for the MF exposure (p 0.015). The number of animals bearing malignant tumours was low and similar in all exposure groups. Epidermal cysts (EC) appeared to be strongly associated with both MF exposure and high ODC activity (transgenic animals). However, EC are not known to be associated with carcinogenesis. The UV-only or combined UV and MF exposure did not affect the ODC activities measured at the end of the exposure. Conclusions: These results support the proposed tumour-promoting effect of MF, but do not suggest an important role for increased ODC activity in this process.

Effects of chronically elevated growth hormone levels on polyamine metabolism in elderly transgenic mice

The polyamines are ubiquitous, multifunctional aliphatic amines with roles in cell growth, proliferation, differentiation, and malignant development. After growth stimulation, rapid and transient changes occur in polyamine regulatory enzymes. In this respect, acute effects of growth hormone (GH) injection on polyamine metabolic enzymes have earlier been shown. The present investigation comprises studies of the effects on polyamine metabolism of constitutively elevated levels of circulating GH in elderly transgenic (tg +) mice, overexpressing bovine GH. Polyamine levels were found to be constitutively altered in the liver and kidney of tg + mice. Less changes were found in the spleen and none in the brain. The cellular uptake of polyamines in the liver from tg + mice showed an increase and considerable changes were observed in the activity of ornithine decarboxylase (ODC) in the liver and kidney and S-adenosylmethionine decarboxylase (AdoMetDC) in the liver. A conspicuous finding was the distribution pattern of ODC protein in the liver in both tg − and tg + animals. The results show that the effects of chronically elevated GH levels are organ-dependent and complex, and differ from acute GH effects. Despite high ODC activity and polyamine levels in liver, these mice did not display any malignant transformation even at an advanced age, indicating that high ODC activity is not sufficient to induce tumorigenesis in vivo.

The Effects of Certain Vitamins and Natural Anti‐oxidants on Ornithine Decarboxylase Activity and on Atrophic and Premalignant Changes in the Human Gastric Mucosa

The effects of beta‐carotene, vitamin E and a pharmaceutical complex of natural anti‐oxidants (OXY‐GARD) on abnormally high ornithine decarboxylase (ODC) activity in antral gastric mucosa of patients with atrophic gastritis (AG), accompanied by intestinal metaplasia (IM), were studied in a randomized placebo‐controlled clinical trial. In cases with H. pylori infection, preliminary eradication of this bacterium was carried out utilizing a standard chemotherapeutic schedule (de nol+metronidazole+oxytetracycline). Efficient eradication of H. pylori resulted in an ODC activity decrease of 16%, on average. It was shown that supplementation with beta‐carotene, at a daily dose of 20 mg, or with vitamin E, at a daily dose of 400 IU, produced decreases in ODC activity of 46% and 44%, respectively, by three months. Daily supplementation with 1 or 2 capsules of OXY‐GARD for three months resulted in ODC activity decreases of 23% and 48%, respectively. Taking into account that abnormally high ODC activity is associated with a high oncogenic potential and plays a specific role in tumor promotion, it is reasonable to suggest that beta‐carotene, vitamin E and OXY‐GARD act in atrophic or premalignant gastric mucosa as anti‐promoters.Preliminary data indicate that prolonged administration of these nutritional supplements, e.g. beta‐carotene for one year, to IM patients produces the maximum decrease in ODC activity at three months. We found that this decrease was accompanied by a delayed partial regression of IM in nine of 18 patients (response rate 50%, 95% confidence interval 26–74%). A study on the effects of long‐term vitamin E or OXY‐GARD supplementation on IM regression is currently in progress. (Dig Endosc 1996 ; 8 : 184–191)

Ornithine decarboxylase: An indicator for growth of NIH 3T3 fibroblasts and their c-Ha- ras transformants

Growth rates of different clones, all derived from NIH 3T3 mouse fibroblasts, were determined. Four different types of cells were studied: (1) Normal NIH 3T3 fibroblasts; (2) a fast-growing NIH 3T3 clone obtained by repeated passages; (3) transformed clones (obtained by transfecting NIH 3T3 with the oncogene c-Ha- ras); (4) a slow-growing revertant obtained by repeated passages of the transformed line. Growth rates were determined by the following markers of proliferation: thymidine incorporation, protein accumulation and cell number. In parallel experiments growth rates were determined by a new approach based on measuring ornithine decarboxylase (ODC) activity. Transformed cells, which were characterized by phase-contrast microscopy and by electron microscopy grew rapidly and showed high ODC activity. Similarly, a high-passage NIH 3T3 variant, which grew rapidly, also possesed high ODC activity. On the other hand, high-passage of a transformed clone revealed phenotypic changes confirmed by electron microscopy. These cells exhibited reduced growth rates and their ODC activities were similar to those of the normal NIH 3T3 cells. A confident correlation was found among each of the three conventional parameters of growth and between them and ODC activity. However, in all the cases studied ODC activity appeared early in the cell cycle before the expression of the other markers of proliferation. It has been suggested that ODC is a reliable early marker of cell proliferation and might also serve as an important tool for determining the arrest of growth.

Consequences of aberrant ornithine decarboxylase regulation in rat hepatoma cells.

DH23A cells, an alpha-difluoromethylornithine (DFMO)-resistant variant of rat hepatoma tissue culture cells (HTC), contain high levels of very stable ornithine decarboxylase (ODC). In the absence of DFMO, the high ODC activity results in a large accumulation of endogenous putrescine. Concomitant with the putrescine increase is a period of cytostasis and a subsequent loss of viable cells. In contrast, HTC cells with a moderate polyamine content can be maintained in exponential growth. This suggests that a moderate polyamine concentration is necessary for both optimal cell growth and survival. The cytotoxicity observed in the DH23A cells is apparently not due to byproducts of polyamine oxidation or alterations in steady state intracellular pH or free [Ca2+]. It is possible to mimic the effects of high levels of stable ODC by treatment of cells with exogenous putrescine in the presence of DFMO. This suggests that overaccumulation of putrescine is the causative agent in the observed cytotoxicity, although the mechanism is unclear. These data support the hypothesis that downregulation of ODC may be necessary to prevent accumulation of cytotoxic concentrations of the polyamines.

Ornithine decarboxylase and malignant growth

There is indirect evidence that key enzymes which catalyse both synthesis and degradation of polyamines (PA) may be useful as biological markers of malignant growth. Ornithine decarboxylase (ODC) activity was assessed in fetal, regenerating and adult rat liver, in hepatoma with different growth rate, in Morris hepatoma cell lines and in rat liver in the course of nitrosopiperidine (NP) carcinogenesis. A much higher ODC activity was observed in all the investigated tumor tissues and in regenerating rat liver as well. A significant decrease of ODC inductive synthesis was demonstrated both in liver and hepatoma of rats maintained on vitamin B6-deficient diet. The experimental suggest that inductive synthesis of ODC may be considered not only early, but also the mandatory event in any hyperproliferating processes including carcinogenesis.

Effects of gastrin and difluoromethylornithine on growth of human colon cancer.

The effect of difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase activity, was evaluated in vivo and in vitro on the growth of a gastrin-sensitive human colon carcinoma (WiDr). In vivo, mice bearing the tumor treated with pentagastrin had larger tumors with higher ornithine decarboxylase activity and polyamine content (P < 0.05) than mice not treated with pentagastrin. Difluoromethylornithine treatment significantly decreased ornithine decarboxylase in both the pentagastrin-treated and the untreated animals; however, DFMO had no effect on tumor volume, weight, protein, or DNA content. In cell culture, gastrin treatment increased WiDr cell number and [3H]thymidine incorporation in the presence or absence of serum. In serum-free conditions, however, gastrin stimulated cell growth without concomitantly increasing ODC activity. DFMO, on the other hand, decreased both ODC activity and growth. These studies suggest that the trophic effect of gastrin on WiDr human colon cancer is independent of ODC activity. Since gastrin treatment increased ODC activity in vivo, gastrin may interact in vitro with other factors present in serum that can alter ODC activity.

Elevated ornithine decarboxylase activity, polyamines and cell proliferation in neoplastic and vacuolated liver cells of winter flounder (Pleuronectes americanus)

Liver neoplasms, including hepatocellular and cholangiocellular tumors, commonly occur in winter flounder (Pleuronectes americanus) caught from some chemically contaminated areas such as Boston Harbor. Hydropically vacuolated cells, very often associated with neoplasia in winter flounder liver, appear to represent the first cellular abnormality in animals that later develop frank neoplasms. The proliferative capacity of hydropically vacuolated cells was studied by analyzing both ornithine decarboxylase (ODC) activity and bromodeoxyuridine (BrdU) labeling indices. Liver of winter flounder with vacuolated cellular lesions had ODC activity more than 5- to 12-fold greater than that in liver that lacked such vacuolation, whether caught from Boston Harbor or Georges Bank. Large focal areas of hydropically vacuolated cells dissected from severely affected livers had ODC activity as high or higher than surrounding parenchymal tissue. Significant elevations in hepatic polyamine levels and ratios of putrescine/spermidine were also present in all Boston Harbor animals studied, especially those exhibiting vacuolated cellular lesions, as compared to Georges Bank fish. BrdU labeling techniques indicate that hydropically vacuolated cells, along with perivacuolar small basophilic cells and neoplastic cholangiocytes, appear to have the capacity to synthesize DNA and undergo mitosis. The frequent association of hydropically vacuolated cells with hepatic neoplasia, along with high ODC activity and DNA synthesis capability, suggest that the vacuolated cells and/or perivacuolar basophilic cells may be integral to the development of some neoplastic phenotypes in winter flounder liver.