Use of transgenic mice as models for prostate cancer chemoprevention

Prostate cancer is a long latency type of tumor that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumor may represent a paradigm for cancer prevention. Several clinical trials have evaluated the effect of different compounds on prostate tumor development, including finasteride, selenium, vitamin E, and carotenes. Although some results are promising, no conclusive data have been achieved as to recommend any of these compounds as preventive agents. Results from some trials, such as SELECT, where supplementation of selenium and/or vitamin-E was used, have been rather disappointing. However, many novel chemopreventive agents that target different cancer-related pathways are being developed lately. Appropriate animal models (in particular, genetically modified mice) are being used to assess the efficacy of these novel compounds. The transgenic adenocarcinoma of the mouse prostate (TRAMP) model has been validated as an accurate model to test a variety of preventive agents. Genistein, alpha-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib, and green tea polyphenols have been shown to prevent prostate cancer development in TRAMP mice. In conclusion, new chemopreventive compounds which are effective in animal models are likely to be tested soon in clinical trials, with the final goal of reducing prostate cancer incidence in men.     

Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery

Several epidemiological studies have demonstrated that vitamin E is a chemopreventative agent for prostate cancer. alpha-Tocopheryl succinate (VES), a derivative of vitamin E, effectively modulates prostate cancer cell growth. However, little is known about the mechanisms regarding this action. Here we show that VES causes human prostate cancer cell LNCaP arrest at G1 phase. This effect is accomplished through VES significantly decreasing expression of the cell cycle regulatory proteins cyclin D1, D3, and E, cdk2 and 4, but not cdk6. Furthermore, VES reduces cdk4 kinase activity, Rb phosphorylation, and cyclin E mRNA expression. Recently there is increasing interest in the protective effect of the VES and selenium combination on prostate cancer. Here we show that VES and selenium work through different mechanisms to exert their inhibitory effects on prostate cancer cells. Taken together, our studies suggest that VES-mediated prostate cancer cell G1/S arrest is a consequence of the regulation of multiple molecules of the cell cycle regulatory machinery.     

A report of high-dose selenium supplementation: response and toxicities.

Concerns about the toxicity of selenium has limited the doses used in chemoprevention. Based on previous studies, intakes of 400 microg/day and plasma selenium of 1000 ng/ml (Dietary Reference Intakes, Academy Press, New York, 2000, p. 384) were established as the no observed adverse effect level (NOAEL). This investigation summarizes the plasma response and toxicity reports from 24 men with biopsy-proven prostate cancer who were randomized to either 1600 or 3200 microg/day of selenized yeast as part of a controlled clinical trial testing selenium as a chemopreventive agent for prostate cancer progression. Subjects were on these doses for averages of almost 12 months. Plasma selenium levels were monitored throughout the course of follow-up. Symptoms of selenium toxicity were assessed by patient interview with specific questions regarding breath, hair and nail changes. Several liver and kidney function tests and hematology were measured at 6-month intervals. 8 subjects were randomized to the 1600 microg/day and 16 to the 3200 microg/day group. The mean plasma selenium levels achieved with supplementation were 492.2 ng/ml (SD = 188.3) and 639.7 ng/ml (SD = 490.7) for the 1600 and 3200 microg/ day doses, respectively. The 3200 microg/day group reported more selenium-related side effects. Blood chemistry and hematology results were all within normal limits for both treatment groups. More subjects on 3200 microg/day reported symptoms of selenium toxicity; however, these reports did not correspond to peaks in plasma selenium levels. We observed no obvious selenium-related serious toxicities. As selenium is used in more chemoprevention and therapeutic settings, additional information on selenium species, sequestration of selenium in specific organs, excretion, and toxicities is needed.     

Selenium and sulfur in antioxidant protective systems: relationships with vitamin E and malaria.

The metabolic relationships among the antioxidant nutrients selenium, sulfur, and vitamin E are particularly close. Selenium and vitamin E have long been known to spare one another in certain nutritional diseases of animals, and selenium has been considered to have a key antioxidant defense function as a component of glutathione peroxidase. However, the antioxidant role of glutathione peroxidase has been questioned and new proteins containing selenium have been identified: phospholipid hydroperoxide glutathione peroxidase, selenoprotein P, and iodothyronine deiodinase. Glutathione peroxidase activity independent of selenium resides in the glutathione S-transferases. Glutathione participates in both enzymatic and nonenzymatic antioxidant defense systems. Some low-molecular weight selenium compounds (e.g., ebselen) exhibit glutathione peroxidase-like action. Certain low molecular weight thiols decompose peroxides nonenzymatically (e.g., the ovothiols). Murine malaria appears to be a useful experimental model for investigating interrelationships of selenium and vitamin E. Vitamin E deficiency protects against the parasite, especially when the mice are concurrently fed peroxidizable fat such as fish or linseed oils. Selenium deficiency, on the other hand, has little or no protective effect against the parasite. Any practical utility of pro-oxidant diets in combating human malaria remains to be determined.     

Influence of vitamin E and selenium on immune response mechanisms.

Vitamin E and selenium have both been shown to have immunostimulatory effects in a variety of species when administered in quantities in excess of established deitary requirements. Responses to each nutrient appeared to be independent of the nutrition of the other. Deficiencies of vitamin E and selenium conversely caused suppression of the immune response system, particularly, cell mediated mechanisms. Suppression was shown to be associated with serum factors coating lymphocytes from dogs deficient in vitamin E and selenium. Oral supplementation with vitamin E transformed or removed the suppressive factors, dietary selenium had no effect. In vitro peripheral lymphocyte blast transformation tests corroborated observations of in vivo studies. Reducing agents and synthetic anti-oxidants eliminated suppressive effects in vitro. Suppression was most marked in dogs fed diets highest in polyunsaturated fatty acid (PUFA) content, providing conditions most conductive to lipid peroxidation in vivo. The essential fatty acids linoleic and arachidonic have been shown to similarly influence immunoregulatory mechanisms in vivo. The effect may be a direct one since plasma membrane fluidity of lymphoid cells increases the probability of modification of cell--antigen interactions by PUFA. However, their effect may also be an indirect one. PUFA are known precursor substances of E anf F type prostaglandins which have been shown to affect immediate and delayed hypersensitivity by stimulating synthesis of cyclic AMP. More definitive studies are needed to resolve this question.     

Selenium as an adjuvant for modification of radiation response

Ionizing radiation plays a central role in several medical and industrial purposes. In spite of the beneficial effects of ionizing radiation, there are some concerns related to accidental exposure that could pose a threat to the lives of exposed people. This issue is also very critical for triage of injured people in a possible terror event or nuclear disaster. The most common side effects of ionizing radiation are experienced in cancer patients who had undergone radiotherapy. For complete eradication of tumors, there is a need for high doses of ionizing radiation. However, these high doses lead to severe toxicities in adjacent organs. Management of normal tissue toxicity may be achieved via modulation of radiation responses in both normal and malignant cells. It has been suggested that treatment of patients with some adjuvant agents may be useful for amelioration of radiation toxicity or sensitization of tumor cells. However, there are always some concerns for possible severe toxicities and protection of tumor cells, which in turn affect radiotherapy outcomes. Selenium is a trace element in the body that has shown potent antioxidant and radioprotective effects for many years. Selenium can potently stimulate antioxidant defense of cells, especially via upregulation of glutathione (GSH) level and glutathione peroxidase activity. Some studies in recent years have shown that selenium is able to mitigate radiation toxicity when administered after exposure. These studies suggest that selenium may be a useful radiomitigator for an accidental radiation event. Molecular and cellular studies have revealed that selenium protects different normal cells against radiation, while it may sensitize tumor cells. These differential effects of selenium have also been revealed in some clinical studies. In the present study, we aimed to review the radiomitigative and radioprotective effects of selenium on normal cells/tissues, as well as its radiosensitive effect on cancer cells.     

Molecular chemoprevention by selenium: a genomic approach

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.     

Aldehyde and Xanthine Oxidase Activities in Tissues of Streptozotocin-Induced Diabetic Rats: Effects of Vitamin E and Selenium Supplementation

Effects of vitamin E and selenium supplementation on aldehyde oxidase (AO) and xanthine oxidase (XO) activities and antioxidant status in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats were examined. AO and XO activities increased significantly after induction of diabetes in rats. Following oral vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) intake once a day for 4 weeks, XO activity decreased significantly. AO activity decreased significantly in liver, but remained unchanged in kidney and heart of vitamin E- and selenium-treated rats compared to the diabetic rats. Total antioxidants status, paraoxonase-1 (PON1) and erythrocyte superoxide dismutase activities significantly decreased in the diabetic rats compared to the controls, while a higher fasting plasma glucose level was observed in the diabetic animals. The glutathione peroxidase activity remained statistically unchanged. Malondialdehyde and oxidized low-density lipoprotein levels were higher in the diabetic animals; however, these values were significantly reduced following vitamin E and selenium supplementation. In summary, both AO and XO activities increase in STZ-induced diabetic rats, and vitamin E and selenium supplementation can reduce these activities. The results also indicate that administration of vitamin E and selenium has hypolipidemic, hypoglycemic, and antioxidative effects. It decreases tissue damages in diabetic rats, too.     

Effect of Sodium Selenite on Gene Expression of SELF,SELW, and TGR Selenoproteins in Adenocarcinoma Cells of the Human Prostate

Selenium is an essential trace element, the deficiency of which leads to the development of several serious diseases, including male infertility, prostate cancer, etc. It has been shown that oxidative stress contributes to the progression of prostate cancer, and antioxidants such as selenium and vitamin E can significantly reduce the risk of this disease. Sodium selenite, one of the selenium compounds that induce the formation of reactive oxygen species, is considered as a potential anticancer agent. The SS concentrations that lead to a decrease in the viability of human prostate adenocarcinoma cells (line Du-145) have been selected, and the effect of sodium selenite on the expression of mRNA of the SELV, SELW, and TGR selenocysteine proteins in these cells has been analyzed.     

Selenium and Vitamin E Modulates Radiation-Induced Liver Toxicity in Pregnant and Nonpregnant Rat: Effects of Colemanite and Hematite Shielding

The levels of liver lipid peroxidation, glutathione peroxidase, reduced glutathione, and vitamins A and E were used to follow the level of oxidative damage caused by ionizing radiation in pregnant rats. The possible protective effects of selenium and vitamin E supplemented to rats housed in concrete-protected cages using hematite and colemanite were tested and compared to untreated controls. Ninety-six rats were randomly divided into four main equal groups namely control (A), normal concrete (B), concrete containing colemanite (C), and concrete containing hematite (D). Except group A, all groups exposed to 7 Gy radiation. The four main groups were divided into four subgroups each as follows: subgroups 1 (n?=?6): nonpregnant control rats. Subgroups 2 (n?=?6): selenium and vitamin E combination was intraperitoneally (i.p.) given to the nonpregnant rats for 20 days. Subgroups 3 (n?=?6): pregnant control rats. Subgroups 4 (n?=?6): selenium and vitamin E combination was i.p. given to the pregnant rats for concessive 20 days. Lactate dehydrogenate, alkaline phosphates, and lipid peroxidation values were higher in subgroups 1 and 3 than in no radiation group although glutathione peroxidase and vitamin E levels in liver were lower in radiation group than in no radiation group. Lactate dehydrogenate activity and lipid peroxidation levels were found to be decreased in subgroups 2 and 4 protected with concrete containing hematite and colemanite when compared to subgroup 1 and 3 with normal concrete. The radiation doses in rats housed by concrete without colemanite and hematite exposed radiation clearly showed liver degeneration. In conclusion, selenium and vitamin E supplementations and housing by concrete with colemanite was found to offer protection against gamma-irradiation-induced liver damage and oxidative stress in rats, probably by exerting a protective effect against liver necrosis via its free radical scavenging and membrane stabilizing. Protective effects of colemanite in the liver seem to be more important than in hematite.     

Vitamin E in immunity and reproductive performance in pigs

This review is focused on studies of vitamin E in immunity and reproductive performance in pigs. There are reports that vitamin E can have a positive effect on some parameters of the immune system in pigs. The optimal level of vitamin E needed to improve the immune system has not been determined because of several factors such as the composition of the diet, feed consumption, the rate of animal growth and living conditions or stress. Moreover, the way of action of vitamin E in enhancing immunity is still unclear but according to reports it may have antioxidant properties as well as an immunomodulator effect. In several studies, an increase in litter size and a reduction of preweaning piglet mortality have resulted from increasing dietary vitamin E intake during gestation or by intramuscular injection of vitamin E and/or selenium. However, according to reports, the positive effect of vitamin E on reproductive performance remains unclear due to the low number of animals used in most experiments.     

Chemopreventive trials in urologic cancer

Cancer prevention uses natural, synthetic, or biological chemical agents to reverse, suppress, or prevent carcinogenic progression. Chemoprevention trials are based on the hypothesis that interruption of the biological process involved in carcinogenesis will inhibit this process and, in turn, reduce cancer incidence. Bladder cancer chemoprevention trials demonstrate conflicting findings. Dietary fat, soy protein, garlic, and selenium have been reported to possess anticancer properties in the bladder, but they still remain largely unstudied in vivo. Regarding prostate cancer, vitamin D deficiency was reported to increase risk for the disease, and sunlight exposure is inversely proportional to prostate cancer mortality. The Prostate Cancer Prevention Trial reported a 24.4% prostate cancer incidence with placebo, compared with 18.4% with finasteride, and a reduction of 24.8% over 7 years. Dutasteride, a dual inhibitor of type 1 and type 2 5alpha-reductase, is the subject of the Reduction by Dutasteride of Prostate Cancer Events trial. Results are awaited from that study.     

Effects of Vitamin E and Selenium on Serum Trace and Major Elements in Horses

The combined effects of vitamin E and selenium were studied in native Anatolian horses subject to strenuous exercise. The concentrations of copper, zinc, iron, calcium, potassium, and magnesium were determined in serum by atomic absorption spectrometry in two study groups (n = 25 each), one of which served as untreated controls. After exercising the horses by running 1,500 m in about 7 min, only the copper level and the copper/zinc ratio significantly increased (p < 0.05), but the concentrations of calcium, potassium, iron, and magnesium remained unchanged. In horses treated with vitamin E and selenium, the calcium and potassium levels decreased to levels lower than those of untreated controls before and after exercise. The iron levels were not changed by exercise or treatment alone but increased when the horses had been supplemented and exercised. The copper level and the copper/zinc ration increased as a result of exercise in both treated and untreated horses. These changes suggest that supplementation with vitamin E and selenium had an important effect on the serum concentrations of calcium, potassium, copper, iron, and the copper/zinc ratio.     

Selenium and Vitamin E Modulates Cigarette Smoke Exposure-Induced Oxidative Stress in Blood of Rats

Cigarette smoke contains about 5,000 chemicals that include organic and metallic compounds. The current study was undertaken to investigate the effects of selenium and vitamin E on oxidative stress-induced damage in rats exposed to cigarette smoke. Forty male rats were equally divided into four groups. The first and second groups were used as control and cigarette smoke groups, respectively. Selenium was administered to rats constituting the third group for 27 days. The Se and vitamin E combination was given to animals in fourth group for 27 days. All groups except the control, were exposed to cigarette smoke starting at the third day of the experiment and continuing for 27 days. The blood samples from all groups were taken at the end of 27 days. Plasma lipid peroxidation, triacylglycerol, and total cholesterol levels were higher in the cigarette smoke group than in the control, although erythrocytic superoxide dismutase and glutathione peroxidase activities were lower in the cigarette smoke group than in the control. The plasma lipid peroxidation, triacylglycerol, and total cholesterol levels were lower in cigarette smoke+Se+VE group than in the cigarette smoke group, although erythrocytic superoxide dismutase activity and glutathione peroxidase activity in selenium and vitamin E-administered groups were higher than in the exposed to cigarette smoke group. High-density lipoprotein-cholesterol level was not affect by selenium and vitamin E administrations. In conclusion, selenium and vitamin E seem to have protective effects on the cigarette smoke-induced blood toxicity by supporting the enzymatic antioxidant redox systems.     

Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis

The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O₂^•−) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine.     

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Selenium and selenium-antagonistic elements in nutritional cancer prevention

Selenium is an essential trace element with antioxidative, antimutagenic, antiviral and anticarcinogenic properties. There is increasing evidence that the dietary selenium intakes are sub-optimal in the populations of many countries and that human cancer mortalities would significantly decline if additional selenium was made available either through supplementation or the fortification of certain foods. An important property of selenium is its interaction with other elements that may be present in foods, the water, the workplace and the environment, e.g. As, Cu, Ni, Co, Cr, Mn, Zn, Cd, Sn, Pb, Hg, Bi, Mo, Ag, Au, etc. The sequestration of elements by selenium represents an efficient natural detoxification mechanism for some of these elements but also results in the physiological inactivation of selenium. Animal experiments confirm that the chronic exposure to low levels of these elements abolishes the cancer-protective effect of selenium. Human cancer is likewise significantly determined by the interactions of selenium with other elements, as evidenced by epidemiological, ecological and case-control studies. Cadmium, for example, is a key risk-increasing element for prostate cancer; for breast cancer, Cd, Cr, Zn are mainly contributing; for bronchial cancer (in smelter workers), Cd, As, Cr, Sb, Co, La, all these elements are in a reciprocal relationship with Se. While selenium remains the key cancer-protective trace element, the interpretation of its mode of action necessitates consideration of the effects of selenium antagonistic elements.     

Inhibition of benzo(a)pyrene-induced carcinogenesis by vitamin C alone and by vitamin C/vitamin E and selenium/glutathione

The reduction on peroxidation caused by benzopyrenes by some naturally occurring antineoplastic agents was studied in this experimental work. Inhibition/reduction of experimental carcinogenesis induced by benzo(a)pyrene by vitamin C alone and by vitamin C/vitamin E and selenium/ glutathione was attempted in 224 female Wistar rats divided in four groups. Injected with 10.08 mL benzo(a)pyrene, the animals were treated with some naturally occurring substances like vitamin C alone and a combination of anticarcinogens. By calculating the carcinogenic potency of benzo(a)pyrene and the anticarcinogenic potency of substances used as well as histological examination of developed tumors and survival time of treated animals, it was found that vitamin C exerts a significant anticarcinogenic effect of 8.3 units and that the combination of the two anticarcinogens used produced a significant prolongation of the animals survival time with anticarcinogenic potency of 22.1 and 22.2 units, respectively. This is considered a potent anticarcinogenic effect. The question of an additional supportive administration of such agents complementary to the conventional cancer chemotherapy in humans is raised. Of course, further studies are needed.     

Influence of Diet on Experimental Swine Dysentery. 1. Effects of A Vitamin E and Selenium Deficient Diet Supplemented with 6.8 % Cod Liver Oil

Sixteen growing pigs were fed a vitamin E and selenium deficient diet; half of the animals (Group 2) were given a daily supply of vitamin E and selenium. After having been fed these diets for 53 days, the pigs were infected orally with minced colonic material from cases with typical swine dysentery. This exposure resulted in outbreaks of swine dysentery in both groups. The incubation times were, however, distinctly shorter and the clinical symptoms much more pronounced in Group 1 than in Group 2. The patho^morphological lesions in the colon also differed between the 2 groups. In the pigs of Group 1 evident pseudomembraneous lesions were observed in the spiral colon. In Group 2, the colonic alterations consisted predominantly of a catarrhal enteritis; pseudomembranes occurred in a minor part of colon in only 4 pigs. Both the clinical and the chemical observations and the pathological findings indicated a much better vitamin E and selenium balance in the pigs of Group 2. It is concluded that the treatment with vitamin E and selenium in Group 2 greatly increased resistance to swine dysentery.     

Temporal changes in tissue glutathione in response to chemical form,dose, and duration of selenium treatment

Selenium has been reported to affect glutathione (GSH) concentrations in short-term animal-feeding experiments. Given the central role that this tripeptide plays in maintaining cellular homeostasis, it was hypothesized that perturbations in glutathione metabolism induced by selenium might account for its cancer chemopreventive activity. In the present study, four experiments were conducted in which the effect of acute, short-, or long-term exposure to selenium was assessed. Selenium was provided as either sodium selenite or D,L-selenomethionine. Selenite was observed to induce a biphasic response in total liver GSH. Injected selenium caused an acute reduction in GSH, whereas short-term feeding (up to 8 wk) increased both total GSH and oxidized glutathione (GSSH), an effect that gradually diminished in magnitude with prolonged feeding. Our data suggest that such changes are unlikely to account for the chemopreventive activity of selenium for the following reasons: Perturbations in glutathione metabolism occurred only at doses of selenite that approached toxicity. These doses are higher than what would be required for producing cancer chemoprevention. The transient nature of these changes also contrasts with the need for a continuous supplementation of selenite in suppression of tumorigenesis. Furthermore, selenomethionine was found to have little activity in altering glutathione metabolism, even though it compares favorably with selenite as a cancer chemopreventive agent. Nonetheless, these findings do not discount the possibility that sulfhydryl compounds, such as glutathione, might be used to modify the toxicity and/or enhance the cancer prophylactic activity of selenium compounds.