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The Journal of Nutrition Vol. 128 No. 11 November 1998,
pp. 1845-1854
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263
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ABSTRACT |
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Abstract
Introduction
References
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The article reviews the progress in basic research of selenium and cancer prevention during the past decade. Special emphasis is placed on the following four major areas of discussion: 1) chemical forms of selenium and anticarcinogenic activity; 2) selenium-enriched food; 3) in vitro effects of selenite vs. monomethylated selenium; and 4) aromatic selenium compounds. It is clear that basic research has contributed new knowledge to our understanding of selenium biochemistry, anticancer efficacy and regulation of cell growth. Some of this information could be ready for incorporation into the design of a second-generation selenium trial in humans.
KEY WORDS: selenium biochemistry · cancer prevention · animal models · cell growth regulation
To researchers working in selenium and cancer prevention, the most exciting news in recent years is the finding by Clark et al. (1996) A randomized, placebo-controlled intervention trial is the ultimate test to evaluate the efficacy of an anticancer agent. Before Clark`s publication, there was already persuasive evidence in the literature suggesting a cancer protective effect of selenium in humans. Geographic correlation data in different regions worldwide and in the U.S. have long noted an inverse association between selenium levels in forage crops or diet and cancer mortality rates (Clark et al. 1991 In view of the renewed interest in selenium and cancer, both in the scientific and lay communities, after the publication of Clark's project, it would be timely to examine what has been achieved in basic research during the past decade. The author has been an active participant in the field for many years. A patina of personal perspective is likely to permeate the article. This review is not intended to be all inclusive of every single paper published on the subject. Instead it will focus on four areas that may suggest the direction of our collective effort in the immediate future. In the introductory paragraph of a paper written by Howard Ganther more than 10 years ago (Ganther 1986 One fascinating aspect of selenium biology is related to its extreme potency. Selenium, in the form of selenite or selenomethionine, functions as an essential micronutrient at levels of ~0.1 ppm (mg/kg) in the animal diet, but it becomes a toxin at levels of 8-10 ppm (Jacobs and Frost 1981
The intervention trial of Clark et al. (1996) Although a spectrum of activities has been attributed to selenium in in vitro studies, this section will focus mainly on events that are associated with cell growth inhibition. During the 1980s, there were numerous reports showing that selenite, at concentrations in the micromole range, suppressed cell proliferation in culture and induced cytotoxicity as documented by the standard cell viability assays. This topic was reviewed previously (Ip and Medina 1987
Karam El-Bayoumy was the first to pioneer the research of aromatic selenium compounds in cancer chemoprevention in the 1980s. His idea originated from the need to develop novel reagents with a lower toxicity than that of selenite and selenomethionine. The chronology started with p-methoxybenzeneselenol (Fig. 3). In collaboration with other investigators at the American Health Foundation, El-Bayoumy reported successful tumor inhibition at different sites (liver, colon and kidney) by the feeding of 50 ppm of p-methoxybenzeneselenol (equivalent to ~20 ppm Se) to rats that were treated with the carcinogen azoxymethane (Reddy et al. 1985
The Clark study (Clark et al. 1996
INTRODUCTION
Abstract
Introduction
References
that supplementation of free-living people with selenized brewer's yeast was capable of decreasing the overall cancer morbidity and mortality by nearly 50%. The study was a double-blind, randomized, placebo-controlled trial involving 1312 patients (mostly men) who were recruited initially because of a history of basal cell or squamous cell carcinoma of the skin. Individuals in the treatment arm were given 200 µg Se/d for a mean of 4.5 y (average daily intake in the U.S. is about 100 µg). After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of these non-melanoma skin lesions. However, patients receiving the Se-yeast supplement showed a much lower prevalence of developing and dying from lung, colon or prostate cancer. Statistical analyses verified that the relative risk of cancer incidence in lung, colon and prostate was reduced to 0.54 (P = 0.04), 0.37 (P = 0.002) and 0.42 (P = 0.03), respectively. Despite the fact that these are major cancers in the U.S. population, they could be considered only as secondary endpoints because the trial was originally set up to determine whether selenium would decrease the incidence of skin cancer.
, Schrauzer et al. 1977, Shamberger et al. 1976, Yu et al. 1985). Several prospective and case-control studies also confirmed that people with low blood selenium had an increased risk of cancer (Clark et al. 1984 and 1993, Salonen et al. 1984 and 1985, Willett et al. 1983). Not all selenium and cancer epidemiology investigations produced uniform results because a handful of them failed to find an association (Coates et al. 1988, Knekt et al. 1988, Menkes et al. 1986, Nomura et al. 1987, Ringstad et al. 1988). The discrepancy is not unexpected because epidemiologic designs differ from one another and these diversities are frequently difficult to reconcile. Nonetheless, the potency of selenium is perhaps best exemplified by a meta-analysis of the combined data from a number of studies comparing the significance of serum selenium, retinol, 
-carotene and vitamin E in relation to cancer risk (Comstock et al. 1992). Among these micronutrients, selenium emerged as the factor with the most consistent protective effect.
), he stated that "it is important to keep in mind that the biological activity of selenium is an expression of selenium in a wide variety of chemical compounds, and not the element per se." This message is just as fitting now as ever and could in fact serve as the cornerstone of this review. Incidentally, Ganther has been a long-time collaborator and has contributed in many ways to much of the work in the author`s laboratory.
CHEMICAL FORMS OF SELENIUM AND ANTICARCINOGENIC ACTIVITY
). At the other extreme, selenium deficiency is customarily induced in laboratory animals by the feeding of a specially formulated diet which contains <0.01 ppm Se. It should be clarified at the outset that we will not deal with the effect of selenium deficiency on carcinogenesis. The information in this particular topic is not only sketchy but also inconsistent. For this reason, the review is limited to a discussion of the effect of selenium at levels above dietary requirement, usually in the range of 1-5 ppm Se. More than 90% of the selenium cancer chemoprevention experiments have used either sodium selenite or selenomethionine as the test reagent because they are commercially available. Both of these compounds are known to suppress carcinogenesis in many animal models (Combs 1997, El-Bayoumy 1991, Ip 1986, Medina and Morrison 1988). The effect is not organ specific, because tumor inhibition has been reported in mammary gland, liver, skin, pancreas, esophagus, colon and a few other sites. In general, there is a dose-dependent response, and selenium chemoprevention can be realized in the absence of toxicity.
). Tissue selenium concentrations in blood, liver, kidney and skeletal muscle, on the other hand, were always higher in rats given selenomethionine compared with those given selenite. Therefore the greater total body burden of selenium in selenomethionine-treated rats did not appear to confer a better protection against tumorigenesis. The question that came to mind was whether selenium metabolism is necessary for its anticarcinogenic activity.
). When methionine is limiting, a greater percentage of selenomethionine is incorporated nonspecifically into body proteins in place of methionine (see Fig. 1) because met-tRNA cannot distinguish between methionine and selenomethionine. In other words, the anticarcinogenic activity of selenomethionine is severely compromised in a situation in which it is preferentially compartmentalized into tissue proteins instead of entering the metabolic pathway.
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Fig 1.
Selenium metabolic pathway. Selenomethionine can be incorporated into proteins in place of methionine because it readily acylates Met-tRNA. Alternatively it can be converted through the transsulfuration mechanism to selenocysteine, which in turn is degraded to hydrogen selenide (H2Se) by the enzyme -lyase. In contrast, selenite is metabolized to H2Se via selenodiglutathione and glutathione selenopersulfide. Hydrogen selenide is generally regarded as the precursor for supplying selenium in an active form for the synthesis of selenoproteins. The further metabolism of H2Se involves sequential methylation by S-adenosylmethionine to methylselenol, dimethylselenide and trimethylselenonium ion.
). With a high intake of selenite or selenomethionine, the levels of methylated metabolites, including methylselenol, dimethyl selenide (expired in breath) and trimethylselenonium (excreted in urine), are expected to rise. Through the support of a collaborative research program with Ganther, we conducted a series of studies that were aimed at addressing the following questions: 1) Does selenium have to flow through the intermediary inorganic hydrogen selenide pool for the cancer protective effect to be manifested? 2) Does methylation of selenium enhance or diminish its chemopreventive efficacy? 3) Is the degree of methylation important? Our strategy was to select precursor compounds that were capable of delivering selenium to specific locations along the methylation pathway (Fig. 2). By this approach, we hoped to be able to pinpoint more closely the active intermediate that is involved in cancer protection (Ip and Ganther 1992). For a more detailed discussion of the biochemistry of selenium metabolism and the generation of potential chemopreventive metabolites, readers are urged to refer to a recent review by Ganther and Lawrence (1997).
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Fig 2.
This schematic flow chart shows the main sites at which selenobetaine, Se-methylselenocysteine, selenobetaine methyl ester and dimethylselenoxide enter the selenium metabolic pathway below the H2Se step.
). Se-methylselenocysteine, on the other hand, is converted to methylselenol directly via a -lyase reaction (Foster et al. 1986b), and unlike selenomethionine, it cannot be incorporated nonspecifically into proteins. We found that both selenobetaine and Se-methylselenocysteine were more efficacious than either selenite or selenomethionine in cancer chemoprevention in the range of 1-3 ppm Se (Ip and Ganther 1990 and 1992, Ip et al. 1991).
). After a single oral dose of dimethylselenoxide, ~90% was recovered as exhalable dimethylselenide within a 24-h period (Vadhanavikit et al. 1993). Its facile conversion to dimethylselenide, which was then rapidly eliminated via the breath, could provide a plausible explanation for the low anticancer activity.
). However, the rate of conversion to dimethylselenide might not be as fast as that with dimethylselenoxide. Interestingly, the anticarcinogenic activity of selenobetaine methyl ester was found to be comparable to that of selenobetaine (Ip and Ganther 1990). The metabolic profile studies also provided evidence that di- and trimethylated metabolites were capable of undergoing demethylation (Vadhanavikit et al. 1993). Because of the slower metabolism of selenobetaine methyl ester to dimethylselenide, some reverse traffic of dimethylselenide demethylation might occur, thereby attaining a critical level of methylselenol in this situation. The above explanation was supported by additional data indicating that there was considerably more back conversion to the inorganic H2Se pool from selenobetaine methyl ester than from dimethylselenoxide (Ip and Ganther 1992).
), probably because it was quantitatively excreted in urine (Vadhanavikit et al. 1993). The poor tissue retention of this compound might account for its low biological activity.
). Thus it appeared that the longer alkyl chain homologs might be superior to methyl selenocyanate. This was a novel finding and could offer further clues to the design of more powerful anticancer selenium compounds.
). Contrary to previous reports in which less sophisticated methods were used in determining that selenomethionine was the major constituent in yeast, recent analysis by a state-of-the-art technique of high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS)3 demonstrated that selenomethionine accounted for no more than 20% of all selenium-containing materials (Bird et al. 1997). In addition to selenomethionine, the other compounds that had been identified included selenocystine, Se-methylselenocysteine and selenoethionine (representing ~20%). On top of that, there were several unidentified peaks that combined to represent 40-50% of the total. Thus the selenized yeast actually contains a cocktail of selenium in a variety of chemical forms. Among these, we have some understanding only of selenomethionine and Se-methylselenocysteine. At this time, there are no data regarding whether these different compounds exert distinctive effects on cell biology or how they might differentially affect the multistep process of carcinogenesis. Translational research generally involves the flow of applied learning from laboratories to clinics. In selenium cancer prevention, we have an unusual scenario in which a human trial ironically magnifies the paucity of knowledge in basic science.
RESEARCH ON SELENIUM-ENRICHED GARLIC
is a classic example of "targeted chemoprevention" in which a particular substance is given to high risk individuals for the purpose of reducing cancer morbidity. There is a second concept of chemoprevention that is aimed at providing cancer protective chemicals to large segments of the population that are not at an increased risk because of known exposure to carcinogens, genetic predisposition or prior diagnosis of malignancy. Because of the intrinsic requirement of this plan for a wide distribution method, an expeditious way of delivering these protective agents is through the food system. Incidentally, a driving force for general population chemoprevention can be traced to the mounting epidemiologic and experimental data that strongly suggest the beneficial effects of various plant constituents present in our diet.
). In the early 1990s, Ip and Lisk started a project in which they tried to enrich garlic with selenium by fertilizing the crop with water-soluble selenite salt. The idea was stimulated by the fact that plants are known to convert inorganic selenium in soil to organic selenium compounds following the sulfur assimilatory pathway (Shrift 1973). Because garlic contains an abundance of sulfur derivatives, it might be able to accumulate high levels of selenium. Initially, our goal was to see whether the idea could be put into practice and if so, to characterize the biological activities of this Se-garlic.
). We have published a series of papers with this material. Selected findings from these studies are summarized below.
and 1994b). Total tumor yield was consistently reduced by 50-60% with 2 ppm Se supplementation. To ascertain that the efficacy of Se-garlic in cancer protection was primarily dependent on the action of selenium, we compared the effects of two batches of garlic powder with different levels of selenium enrichment, 112 vs. 1355 ppm Se dry weight. To achieve 2 ppm Se in the diet with these two batches of garlic powder, the amount needed was 1.8% for the 112 ppm Se-garlic vs. 0.15% for the 1355 ppm Se-garlic. In this way, we could vary the intake of garlic powder by more than 10-fold but keep the intake of total selenium constant. The results from several experiments led to the conclusion that the anticancer activity of Se-garlic was primarily accounted for by the effect of selenium, rather than the effect of garlic per se (Ip and Lisk 1995).
). DMBA is a procarcinogen requiring metabolic conversion to the ultimate carcinogen, DMBA-3,4-diol-1,2-epoxide, which then reacts with DNA to form adducts (Dipple et al. 1983, Liu and Milner 1992). Adduct formation is therefore the first manifestation of genotoxicity by the initiated cells. After absorption from the intestinal tract, DMBA undergoes first-pass metabolism in the liver. Although the liver is not a target site for DMBA-induced carcinogenesis, DMBA adducts are known to be present in liver DNA. After leaving the liver, some of the activated DMBA metabolites travel via the circulation to the mammary gland. Thus an analysis of DMBA adducts in both mammary cells and liver would provide confirmatory information of changes in DMBA metabolism. Our research showed that three types of adducts, anti-dG, anti-dA and syn-dA, were detected in mammary gland, whereas only the first two adducts were found in liver. Prior treatment with Se-garlic resulted in a consistent reduction of all DMBA-DNA adducts in both tissues (Ip and Lisk 1995 and 1997), suggesting that Se-garlic interfered with DMBA in causing genotoxic damage to DNA.
). Thus a reduction in the activity of P450 1A1 would be expected to cause a decrease in adduct levels. Defenses against carcinogenic injury, on the other hand, are provided by phase II enzymes [such as glutathione-S-transferase and uridine diphosphate (UDP)-glucuronyltransferase], which are involved in the removal of metabolites through conjugation with glutathione or glucuronic acid (Talalay 1992). An increase in the activity of these phase II detoxifying enzymes could diminish the availability of DMBA metabolites in interacting with DNA.
). In contrast, glutathione-S-transferase and UDP-glucuronyltransferase were elevated to a maximum of 2- to 2.5-fold in liver and kidney in a dose-dependent manner (Ip and Lisk 1997). Our data therefore implied that an increased detoxification of carcinogen via the phase II conjugating enzymes might represent a mechanism of tumor suppression by Se-garlic.
), suggesting that Se-garlic might irreversibly suppress the clonal expansion of transformed cells in their early stage of development. Plasma and mammary tissue selenium levels essentially returned to basal values within a few weeks after withdrawal of Se-garlic supplementation. Thus the outcome of cancer protection by the short-term intervention regimen was not due to a slow turnover and thus a lingering presence of selenium in the target organ or in the circulation.
). There is a specific structure called the terminal end bud, which is the primary site for the induction of mammary carcinoma. Within 2-3 wk after carcinogen dosing, enlargement of the terminal end bud, characterized by a localized piling up of intraductal cells, is detectable in histological sections. These transformed cells continue to proliferate until they fill up the duct. This type of preneoplastic lesions, known as "intraductal proliferations" or IDP, is the precursor for the eventual development of palpable carcinomas. Se-garlic could conceivably inhibit or even eliminate these IDP, thereby reducing the number of premalignant lesions that are normally present in the early stage of mammary carcinogenesis. Preliminary studies from our laboratory indicated that the total number of IDP was reduced by 50% in the Se-garlic fed rats 6 wk after MNU treatment (unpublished). This observation reinforces our belief that the IDP are likely to be the target sites of selenium chemoprevention.
). Unlike selenomethionine, which produced large increases in tissue selenium accumulation, Se-garlic caused only modest elevations (Ip and Lisk 1996). These attributes of Se-garlic became clear when Se-methylselenocysteine was identified as the major selenium-containing constituent in Se-garlic (Cai et al. 1995). The discovery was made through a collaboration between the laboratories of Peter Uden and Eric Block. Considering that the Se-methylselenocysteine research (discussed in the last section) was done before the inception of the Se-garlic project, everything came around in full circle, although the coincidence was rather fortuitous.
). At higher levels, it has potent anticancer activity but does not cause excessive selenium accumulation because its predominant organoselenium compound, Se-methylselenocysteine, is rapidly metabolized to di- and trimethylated excretory products (Fig. 2). It induces phase II detoxifying enzymes, thereby facilitating the endogenous removal of xenobiotics. Most interesting of all, it appears to block the development of preneoplastic lesions. This mode of action is particularly suitable for reducing cancer morbidity in sporadic cases. Because Se-methylselenocysteine cannot be incorporated nonspecifically into proteins, the amount of total selenium decays quickly from various tissues upon discontinuation of Se-garlic feeding. The lack of a persistent retention in the body might alleviate the concern of selenosis in humans.
IN VITRO EFFECTS OF SELENITE AND METHYLATED FORMS OF SELENIUM
, Medina and Morrison 1988). At that time, selenite was the compound of choice because it was easily available from commercial sources. When the research was shifted to the methylated selenium compounds in the early 1990s, the laboratory of Henry Thompson began generating a body of information that supported the concept of distinctive cellular responses to specific chemical forms of selenium. The work of Thompson and co-workers resulted in a series of papers that were aimed primarily at comparing the in vitro activities of selenite with that of methylselenocyanate or Se-methylselenocysteine (Jiang et al. 1993, Kaeck et al. 1997, Lu et al. 1994, 1995b and 1996, Wilson et al. 1992).
View this table:
Table 1.
In vitro effects of selenite and methylated forms of selenium1
, Weinberg 1995). There are two recent studies from Medina's laboratory describing a link between selenium and cell cycle proteins. In the first study, which involved the use of an asynchronized mammary epithelial cell culture model (Sinha et al. 1996), it was found that Se-methylselenocysteine caused a 57% drop in cdk2 kinase activity and a 74% decrease in cyclin E-cdk2 content (therefore compatible with a G1 arrest observed in this study as well as in the studies of Thompson), whereas selenite actually increased the cdk2 kinase activity by 47% without much appreciable change (10-20% decrease) in either of the cyclins D1, E or A bound to cdk2. The selenite results were incongruous with a S/G2-M arrest, suggesting that the inhibition of cell growth by selenite might be associated with some nonspecific genotoxic effect unrelated to regulation of cell cycle proteins.
) of cell cycling disruption were done at a single time point in cells that were not synchronized, thus making it difficult to elucidate whether the cell cycle clock was stopped or delayed. Synchronized cells, on the other hand, are able to provide more precise information on the timing of the cell cycle clock with respect to other cellular events. With this in mind, Sinha and Medina (1997) repeated the experiments with cells that were released from growth factor deprivation by refeeding them with regular medium, a method commonly employed for synchronization. Parallel cultures were set up so that the cells could be sampled at different time points. [3H]Thymidine incorporation into control cells peaked 16 h after refeeding. At this time point, 60% of cells had entered the S phase. Se-Methylselenocysteine, which was added to the medium 6 h after refeeding, inhibited [3H]thymidine incorporation by ~50% and caused a significant delay in the S phase for almost 18 h. It also produced a concomitant 54% reduction in cdk2 kinase activity (confirming the finding of the previous study). A decrease in cdk2 kinase would be expected to impede progress through the S phase. The level of cyclin E associated with cdk2 did show a transient decrease at an early time point, but it recovered, thereby allowing cells to cross the G1/S boundary (recall the persistent decrease in cyclin E-cdk2 in asynchronized cells). In summary, the data demonstrated that inhibition of cell growth by Se-methylselenocysteine was due to a prolonged delay in the S phase that was coincident with a marked decrease in cdk2 kinase activity.
tried to quantitate the proportion of apoptotic cells by the Apoptag method in a human colon cancer cell line treated with 10 µmol/L selenite. After 4 d, they found that as many as 40% of the cells were stained positive with the use of this assay, which is based on immunohistochemical detection of digoxigenin-labeled nucleotides added to the free 3'-hydroxyl ends generated as a result of DNA breaks. Because 5-10 µmol/L selenite is known to produce massive DNA strand breaks independently of apoptosis, the results of this study are difficult to interpret. Selenodiglutathione, a metabolite of selenite (Fig. 1), has also been examined by a different group of investigators. Lanfear et al. (1994) showed that selenodiglutathione was able to induce apoptosis as determined by fluorescence dye DNA-binding analysis. The principle of the assay is based on the discrimination that apoptotic cells will bind only the Hoechst 33342 dye, whereas necrotic cells will bind both the Hoechst dye and propidium iodide. Live cells do not bind either dye and therefore do not fluoresce. The different subpopulations can be sorted by flow cytometry based on their blue (Hoechst) or red (propidium iodide) fluorescence signals.
) and for the effect of selenomethionine in HT29 colon cancer cells, which express a mutated p53 (Redman et al. 1997). Given that mutations in p53 are among the most common pathogenetic alterations in human cancers (Greenblatt 1994), an intervention mechanism based on the induction of apoptosis could provide a strong rationale for selenium chemoprevention in the human population. Further research should be focused on testing this hypothesis in vivo and on developing appropriate biomarkers associated with the control of apoptosis.
AROMATIC SELENIUM COMPOUNDS
, Tanaka et al. 1985). This compound, however, was quickly abandoned in favor of benzylselenocyanate (Fig. 3), even though benzylselenocyanate was apparently more toxic. The dosage that causes 50% mortality (LD50) of p-methoxybenzeneselenol and benzylselenocyanate in mice was 370 and 18 mg/kg body weight, respectively (El-Bayoumy 1985). Subsquent studies with benzylselenocyanate (El-Bayoumy 1985, Nayini et al. 1989 and 1991) showed that it suppressed tumorigenesis in several models including forestomach (benzo[a]pyrene), colon (azoxymethane) and mammary gland (DMBA). The carcinogen responsible for inducing cancer at each site is denoted parenthetically. In the above experiments, benzylselenocyanate was given in the diet at a concentration of 25 ppm (equivalent to 10 ppm Se); the schedule generally encompassed a relatively short time period, which started 2 wk before to 1 wk after carcinogen administration. The sulfur analog, benzylthiocyanate, was not effective, suggesting that there was specificity to selenium chemoprevention. The fact that benzylselenocyanate is able to block tumor induction by a variety of carcinogens at the initiation stage is intriguing because different P450 families are involved in the activation of benzo[a]pyrene, azoxymethane and DMBA. In the case of azoxymethane, Fiala et al. (1991) found that benzylselenocyanate increased its oxidative metabolism in the liver, thus resulting in a reduced delivery of methylazoxymethanol to the colon via the bloodstream. Consequently, there was less DNA alkylation in the colon, which was reflected by a diminished formation of O6-methylguanine and 7-methylguanine. As far as the author is aware, the effect of benzylselenocyanate on polycyclic hydrocarbon metabolism has not been investigated.
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Fig 3.
Structures of aromatic selenium compounds.
). A level of 80 ppm of pXSC (equivalent to 40 ppm Se) inhibited DMBA-induced mammary carcinogenesis in the initiation stage by suppressing the formation of DMBA-DNA adducts (El-Bayoumy et al. 1992). Whether this was due to modulation of P450 enzymes or phase II detoxifying enzymes remains to be determined. The anti-initiation effect was similarly observed in the azoxymethane-induced colon cancer model (Reddy et al. 1992). Additionally, pXSC also inhibited mammary and colon carcinogenesis in the postinitiation or tumor promotion phase (Ip et al. 1994a, Reddy et al. 1992), suggesting that it may have multiple mechanisms of action. Interestingly, prostaglandin E2 was marginally decreased, whereas glutathione peroxidase was significantly increased in the colon of pXSC-treated rats. The significance of these findings with respect to cancer chemoprevention is unclear at the present time.
). NNK, which stands for 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, is a tobacco-specific carcinogen. pXSC at levels of 5, 10 and 15 ppm Se significantly reduced lung tumor multiplicity from 7.6 per mouse in the control group to 4.1, 3.3 and 1.8 per mouse, respectively. In contrast, selenite at 5 ppm Se had no protective effect. Consistent with the findings of these bioassays were the observations that pXSC decreased NNK-induced O6-methylguanine formation in lung DNA, whereas selenite failed to produce a similar response (Prokopczyk et al. 1996). In rodents, 
-hydroxylation of NNK is a major pathway of NNK metabolism (Hecht 1994). This key reaction leads to the formation of electrophiles, which can readily methylate and pyridyloxobutylate various macromolecules. The bioactivation of NNK is catalyzed by multiple P450 enzymes including 1A1, 2A1, 2B1, 2B2 and others that have not been characterized. In view of the fact that NNK is strongly implicated in the pathogenesis of tobacco-related lung cancer in humans (Hecht and Hoffmann 1988), it is important to elucidate the biochemical mechanisms by which pXSC modulates NNK metabolism as well as that of other nitrosoamines.
). Although the difference in biological activity was small, the isomers were not necessarily absorbed to the same extent by the intestinal tract. After an oral gavage, the percentage dose recovered in the feces in 2 d for o-XSC, m-XSC and p-XSC was 25, 60 and 75%, respectively (Sohn et al. 1995). The pharmacokinetics of these compounds in relation to their potency will have to be investigated more thoroughly.
. However, the rate of selenium release cannot explain entirely the anticarcinogenic activity of pXSC. The study of Ip et al. (1994a) showed that 10 ppm Se as pXSC was equivalent to 3 ppm Se as selenite in the efficacy of cancer protection. On the other hand, it took 1 ppm Se as pXSC to fully replete glutathione peroxidase in a selenium-deficient animal as opposed to only 0.1 ppm Se as selenite. Therefore, the ratio of anticancer activity to nutritional activity for pXSC is 10, as opposed to a ratio of 30 for selenite, suggesting that pXSC has certain inherent activity that is independent of the release of selenium from the parent molecule.
). At a level of 30 ppm Se supplemented in the diet, total tumor yield was suppressed by 60-70% in rats that had been treated with a mammary carcinogen. This dose level produced hardly any accumulation of total selenium in tissues, even under a chronic treatment condition. Preliminary studies indicated that it was very well tolerated by laboratory animals. No evidence of adverse symptoms was detected at levels up to 200 ppm Se. There is thus a wide margin separating the chemopreventive dose range and the toxic dose range. Given the cationic and bulky nature of the molecule, the high tolerance is likely due to a poor rate of absorption via the enteral route. Fecal excretion after a single oral administration of triphenylselenonium was ~78 and 8% of the dose during d 1 and 2, respectively, suggesting that a large proportion of the gavage passed through the intestinal tract with minimal recirculation (Ip et al. 1997). Considering that so little is in fact taken up by the body, the in vivo activity of triphenylselenonium is truly fascinating.
). An agent that does not induce apoptosis will not be expected to cause deletion of transformed cells. Unless it is available continuously, the ability to protect against cancer would be lost when treatment is interrupted. This is the type of response predicted for triphenylselenonium. When triphenylselenonium was given continuously during the entire period of tumor promotion/progression (a 5-mo protocol), it was very effective in suppressing the development of tumors. However, when the treatment period was shortened to 1 mo after carcinogen dosing, there was a marked decrease in efficacy (Ip et al. 1998). At this point, it might be worthwhile to recall the data with Se-garlic in which a 1-mo treatment schedule was just as effective as the 5-mo schedule in cancer protection. As discussed in the previous section, the monomethylated selenium is a potent inducer of apoptosis. The elimination of early transformed preneoplastic cells might explain the outcome of sustaining a lower cancer risk even if treatment is discontinued after a short period of exposure to the anticancer agent.
). At this dose level, diphenylselenide was at best only half as active as triphenylselenonium in tumor inhibition. For diphenylselenide, fecal recovery was ~6 and 30% of the dose during d 1 and 2, respectively, and ~20% of the dose was recovered in the urine on each of the 2 d. The excretion profile suggested that most of the diphenylselenide dose was absorbed and that urinary excretion was a major route of elimination for diphenylselenide once it was absorbed. Even though diphenylselenide caused a two- to threefold increase in tissue selenium, it was less active than triphenylselenonium in cancer protection. The above experiments bring home the message that small changes in the structure of selenium compounds could lead to rather surprising changes in biological activity.
CONCLUSION
) was started in 1984. At that time, very little was known about the mechanism of action of selenium in cancer prevention. Fourteen years later, the gap has been narrowed but there is still a glaring void in our understanding of how selenium might block the clonal expansion of early malignant cells, especially at the molecular level. The science of cancer chemotherapy has long recognized the need to develop a close interaction among chemists, biochemists, pharmacologists, oncologists, pathologists, toxicologists, cell biologists and molecular biologists. Such a concerted enterprise is sorely lacking in the cancer chemoprevention arena. Currently there are hundreds of chemicals that have been and are being evaluated for anticancer activities in both in vivo and in vitro models. The cumulative effort is substantial, but there is little to demonstrate because the effort is so fragmented. Unless the community as a whole (including both commercial and public sectors) is willing to prioritize and commit the necessary resources for targeted research, the work on these hundreds of chemicals will proceed at the same agonizingly slow pace as we cross into the 21st century.
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FOOTNOTES |
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Manuscript received 9 April 1998. Initial reviews completed 27 May 1998. Revision accepted 7 July 1998.
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LITERATURE CITED |
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Abstract
Introduction
References
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a model for cancer prevention strategies.
Drug. Metab. Rev.
1994;
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 H. Zeng, M. Wu, and J. H. Botnen Methylselenol, a Selenium Metabolite, Induces Cell Cycle Arrest in G1 Phase and Apoptosis via the Extracellular-Regulated Kinase 1/2 Pathway and Other Cancer Signaling Genes J. Nutr., September 1, 2009; 139(9): 1613 - 1618. [Abstract] [Full Text] [PDF]
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 L. Wang, M. J.L. Bonorden, G.-x. Li, H.-J. Lee, H. Hu, Y. Zhang, J. D. Liao, M. P. Cleary, and J. Lu Methyl-Selenium Compounds Inhibit Prostate Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model with Survival Benefit Cancer Prevention Research, May 1, 2009; 2(5): 484 - 495. [Abstract] [Full Text] [PDF]
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 W. Jiang, C. Jiang, H. Pei, L. Wang, J. Zhang, H. Hu, and J. Lu In vivo molecular mediators of cancer growth suppression and apoptosis by selenium in mammary and prostate models: lack of involvement of gadd genes Mol. Cancer Ther., March 1, 2009; 8(3): 682 - 691. [Abstract] [Full Text] [PDF]
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 D. L. Hatfield and V. N. Gladyshev The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) Reveals the Need for Better Understanding of Selenium Biology Mol. Interv., February 1, 2009; 9(1): 18 - 21. [Abstract] [Full Text] [PDF]
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 Y. Hu, G. H. McIntosh, R. K. Le Leu, R. Woodman, and G. P. Young Suppression of Colorectal Oncogenesis by Selenium-Enriched Milk Proteins: Apoptosis and K-ras Mutations Cancer Res., June 15, 2008; 68(12): 4936 - 4944. [Abstract] [Full Text] [PDF]
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 J. Jayachandran and S. J. Freedland Prevention of Prostate Cancer: What We Know and Where We Are Going American Journal of Men's Health, June 1, 2008; 2(2): 178 - 189. [Abstract] [PDF]
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 Z. Selamoglu Talas, I. Ozdemir, I. Yilmaz, Y. Gok, and I. Orun The Investigation of the Antioxidative Properties of the Novel Synthetic Organoselenium Compounds in Some Rat Tissues Experimental Biology and Medicine, May 1, 2008; 233(5): 575 - 579. [Abstract] [Full Text] [PDF]
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 G.-x. Li, H.-J. Lee, Z. Wang, H. Hu, J. D. Liao, J. C. Watts, G. F. Combs Jr, and J. Lu Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite Carcinogenesis, May 1, 2008; 29(5): 1005 - 1012. [Abstract] [Full Text] [PDF]
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D. N. Stemm, J. C. Tharappel, H.-J. Lehmler, C. Srinivasan, J. S. Morris, V. L. Spate, L. W. Robertson, B. T. Spear, and H. P. Glauert Effect of Dietary Selenium on the Promotion of Hepatocarcinogenesis by 3,3', 4,4'-Tetrachlorobiphenyl and 2,2', 4,4', 5,5'-Hexachlorobiphenyl Experimental Biology and Medicine, March 1, 2008; 233(3): 366 - 376. [Abstract] [Full Text] [PDF]
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S. Juliger, H. Goenaga-Infante, T. A. Lister, J. Fitzgibbon, and S. P. Joel Chemosensitization of B-Cell Lymphomas by Methylseleninic Acid Involves Nuclear Factor-{kappa}B Inhibition and the Rapid Generation of Other Selenium Species Cancer Res., November 15, 2007; 67(22): 10984 - 10992. [Abstract] [Full Text] [PDF]
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J. Y. Chun, Y. Hu, E. Pinder, J. Wu, F. Li, and A. C. Gao Selenium inhibition of survivin expression by preventing Sp1 binding to its promoter Mol. Cancer Ther., September 1, 2007; 6(9): 2572 - 2580. [Abstract] [Full Text] [PDF]
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 R. D. Mateo, J. E. Spallholz, R. Elder, I. Yoon, and S. W. Kim Efficacy of dietary selenium sources on growth and carcass characteristics of growing-finishing pigs fed diets containing high endogenous selenium J Anim Sci, May 1, 2007; 85(5): 1177 - 1183. [Abstract] [Full Text] [PDF]
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J.-M. Park, A. Kim, J.-H. Oh, and A.-S. Chung Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-{kappa}B activation Carcinogenesis, April 1, 2007; 28(4): 837 - 847. [Abstract] [Full Text] [PDF]
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R. Zhao, F. E. Domann, and W. Zhong Apoptosis induced by selenomethionine and methioninase is superoxide mediated and p53 dependent in human prostate cancer cells Mol. Cancer Ther., December 1, 2006; 5(12): 3275 - 3284. [Abstract] [Full Text] [PDF]
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H. Zeng, M. Briske-Anderson, J. P. Idso, and C. D. Hunt The Selenium Metabolite Methylselenol Inhibits the Migration and Invasion Potential of HT1080 Tumor Cells J. Nutr., June 1, 2006; 136(6): 1528 - 1532. [Abstract] [Full Text] [PDF]
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R. Irons, B. A. Carlson, D. L. Hatfield, and C. D. Davis Both Selenoproteins and Low Molecular Weight Selenocompounds Reduce Colon Cancer Risk in Mice with Genetically Impaired Selenoprotein Expression J. Nutr., May 1, 2006; 136(5): 1311 - 1317. [Abstract] [Full Text] [PDF]
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J. Y. Chun, N. Nadiminty, S. O. Lee, S. A. Onate, W. Lou, and A. C. Gao Mechanisms of selenium down-regulation of androgen receptor signaling in prostate cancer. Mol. Cancer Ther., April 1, 2006; 5(4): 913 - 918. [Abstract] [Full Text] [PDF]
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 A. L. Sabichi, J. J. Lee, R. J. Taylor, I. M. Thompson, B. J. Miles, C. M. Tangen, L. M. Minasian, L. L. Pisters, J. R. Caton, J. W. Basler, et al. Selenium accumulation in prostate tissue during a randomized, controlled short-term trial of l-selenomethionine: a Southwest Oncology Group Study. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2178 - 2184. [Abstract] [Full Text] [PDF]
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 A. Connelly-Frost, C. Poole, J. A. Satia, L. L. Kupper, R. C. Millikan, and R. S. Sandler Selenium, apoptosis, and colorectal adenomas. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 486 - 493. [Abstract] [Full Text] [PDF]
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K. El-Bayoumy, R. Sinha, J. T. Pinto, and R. S. Rivlin Cancer Chemoprevention by Garlic and Garlic-Containing Sulfur and Selenium Compounds J. Nutr., March 1, 2006; 136(3): 864S - 869S. [Abstract] [Full Text] [PDF]
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T. Tsuneyoshi, J. Yoshida, and T. Sasaoka Hydroponic Cultivation Offers A Practical Means of Producing Selenium-Enriched Garlic J. Nutr., March 1, 2006; 136(3): 870S - 872S. [Abstract] [Full Text] [PDF]
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M. G. Fakih, L. Pendyala, P. F. Smith, P. J. Creaven, M. E. Reid, V. Badmaev, R. G. Azrak, J. D. Prey, D. Lawrence, and Y. M. Rustum A Phase I and Pharmacokinetic Study of Fixed-Dose Selenomethionine and Irinotecan in Solid Tumors Clin. Cancer Res., February 15, 2006; 12(4): 1237 - 1244. [Abstract] [Full Text] [PDF]
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Y. Wu, H. Zhang, Y. Dong, Y.-M. Park, and C. Ip Endoplasmic Reticulum Stress Signal Mediators Are Targets of Selenium Action Cancer Res., October 1, 2005; 65(19): 9073 - 9079. [Abstract] [Full Text] [PDF]
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R. G. Azrak, J. Yu, L. Pendyala, P. F. Smith, S. Cao, X. Li, W. D. Shannon, F. A. Durrani, H. L. McLeod, and Y. M. Rustum Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors Mol. Cancer Ther., May 1, 2005; 4(5): 843 - 854. [Abstract] [Full Text] [PDF]
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 S. M. Lyi, L. I. Heller, M. Rutzke, R. M. Welch, L. V. Kochian, and L. Li Molecular and Biochemical Characterization of the Selenocysteine Se-Methyltransferase Gene and Se-Methylselenocysteine Synthesis in Broccoli Plant Physiology, May 1, 2005; 138(1): 409 - 420. [Abstract] [Full Text] [PDF]
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S. O. Lee, N. Nadiminty, X. X. Wu, W. Lou, Y. Dong, C. Ip, S. A. Onate, and A. C. Gao Selenium Disrupts Estrogen Signaling by Altering Estrogen Receptor Expression and Ligand Binding in Human Breast Cancer Cells Cancer Res., April 15, 2005; 65(8): 3487 - 3492. [Abstract] [Full Text] [PDF]
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G. F. Combs Jr Current Evidence and Research Needs to Support a Health Claim for Selenium and Cancer Prevention J. Nutr., February 1, 2005; 135(2): 343 - 347. [Abstract] [Full Text] [PDF]
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 S. M. Lippman, P. J. Goodman, E. A. Klein, H. L. Parnes, I. M. Thompson, A. R. Kristal, R. M. Santella, J. L. Probstfield, C. M. Moinpour, D. Albanes, et al. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT) J Natl Cancer Inst, January 19, 2005; 97(2): 94 - 102. [Abstract] [Full Text] [PDF]
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A.-C. Goulet, M. Chigbrow, P. Frisk, and M. A. Nelson Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells Carcinogenesis, January 1, 2005; 26(1): 109 - 117. [Abstract] [Full Text] [PDF]
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L. Bjorkhem-Bergman, U.-B. Torndal, S. Eken, C. Nystrom, A. Capitanio, E. H. Larsen, M. Bjornstedt, and L. C. Eriksson Selenium prevents tumor development in a rat model for chemical carcinogenesis Carcinogenesis, January 1, 2005; 26(1): 125 - 131. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, N. K. Narayanan, D. Desai, B. Pittman, and B. S. Reddy Effects of a combination of docosahexaenoic acid and 1,4-phenylene bis(methylene) selenocyanate on cyclooxygenase 2, inducible nitric oxide synthase and {beta}-catenin pathways in colon cancer cells Carcinogenesis, December 1, 2004; 25(12): 2443 - 2449. [Abstract] [Full Text] [PDF]
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V. Diwadkar-Navsariwala and A. M. Diamond The Link between Selenium and Chemoprevention: A Case for Selenoproteins J. Nutr., November 1, 2004; 134(11): 2899 - 2902. [Abstract] [Full Text] [PDF]
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J. A. Milner Molecular Targets for Bioactive Food Components J. Nutr., September 1, 2004; 134(9): 2492S - 2498S. [Abstract] [Full Text] [PDF]
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S. D. Cho, C. Jiang, B. Malewicz, Y. Dong, C. Y.F. Young, K.-S. Kang, Y.-S. Lee, C. Ip, and J. Lu Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription Mol. Cancer Ther., May 1, 2004; 3(5): 605 - 612. [Abstract] [Full Text] [PDF]
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S. Cao, F. A. Durrani, and Y. M. Rustum Selective Modulation of the Therapeutic Efficacy of Anticancer Drugs by Selenium Containing Compounds against Human Tumor Xenografts Clin. Cancer Res., April 1, 2004; 10(7): 2561 - 2569. [Abstract] [Full Text] [PDF]
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 M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen Enzyme-Catalyzed Activation of Anticancer Prodrugs Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102. [Abstract] [Full Text] [PDF]
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 H. Zhao, M. L. Whitfield, T. Xu, D. Botstein, and J. D. Brooks Diverse Effects of Methylseleninic Acid on the Transcriptional Program of Human Prostate Cancer Cells Mol. Biol. Cell, February 1, 2004; 15(2): 506 - 519. [Abstract] [Full Text] [PDF]
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K. Zu and C. Ip Synergy between Selenium and Vitamin E in Apoptosis Induction Is Associated with Activation of Distinctive Initiator Caspases in Human Prostate Cancer Cells Cancer Res., October 15, 2003; 63(20): 6988 - 6995. [Abstract] [Full Text] [PDF]
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 N. Kaplan, A. Vaaknin, and M. Linial PANDORA: keyword-based analysis of protein sets by integration of annotation sources Nucleic Acids Res., October 1, 2003; 31(19): 5617 - 5626. [Abstract] [Full Text] [PDF]
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M. J. Jackson, C. S. Broome, and F. MCArdle Marginal Dietary Selenium Intakes in the UK: Are There Functional Consequences? J. Nutr., May 1, 2003; 133(5): 1557S - 1559. [Abstract] [Full Text] [PDF]
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D. J. Waters, S. Shen, D. M. Cooley, D. G. Bostwick, J. Qian, G. F. Combs Jr., L. T. Glickman, C. Oteham, D. Schlittler, and J. S. Morris Effects of Dietary Selenium Supplementation on DNA Damage and Apoptosis in Canine Prostate J Natl Cancer Inst, February 5, 2003; 95(3): 237 - 241. [Abstract] [Full Text] [PDF]
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C. Jiang, Z. Wang, H. Ganther, and J. Lu Distinct Effects of Methylseleninic Acid versus Selenite on Apoptosis, Cell Cycle, and Protein Kinase Pathways in DU145 Human Prostate Cancer Cells Mol. Cancer Ther., October 1, 2002; 1(12): 1059 - 1066. [Abstract] [Full Text] [PDF]
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A. V. Gasparian, Y. J. Yao, J. Lu, A. Y. Yemelyanov, L. A. Lyakh, T. J. Slaga, and I. V. Budunova Selenium Compounds Inhibit I{kappa}B Kinase (IKK) and Nuclear Factor-{kappa}B (NF-{kappa}B) in Prostate Cancer Cells Mol. Cancer Ther., October 1, 2002; 1(12): 1079 - 1087. [Abstract] [Full Text] [PDF]
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 M. Rooseboom, G. Schaaf, J. N. M. Commandeur, N. P. E. Vermeulen, and J. Fink-Gremmels beta -Lyase-Dependent Attenuation of Cisplatin-Mediated Toxicity by Selenocysteine Se-Conjugates in Renal Tubular Cell Lines J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 884 - 892. [Abstract] [Full Text] [PDF]
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 P. D. Whanger Selenocompounds in Plants and Animals and their Biological Significance J. Am. Coll. Nutr., June 1, 2002; 21(3): 223 - 232. [Abstract] [Full Text] [PDF]
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 D.-w. Jeong, M.-H. Yoo, T. S. Kim, J.-H. Kim, and I. Y. Kim Protection of Mice from Allergen-induced Asthma by Selenite. PREVENTION OF EOSINOPHIL INFILTRATION BY INHIBITION OF NF-kappa B ACTIVATION J. Biol. Chem., May 10, 2002; 277(20): 17871 - 17876. [Abstract] [Full Text] [PDF]
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 M. Bebien, G. Lagniel, J. Garin, D. Touati, A. Vermeglio, and J. Labarre Involvement of Superoxide Dismutases in the Response of Escherichia coli to Selenium Oxides J. Bacteriol., March 15, 2002; 184(6): 1556 - 1564. [Abstract] [Full Text] [PDF]
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Y. Dong, H. E. Ganther, C. Stewart, and C. Ip Identification of Molecular Targets Associated with Selenium-induced Growth Inhibition in Human Breast Cells Using cDNA Microarrays Cancer Res., February 1, 2002; 62(3): 708 - 714. [Abstract] [Full Text] [PDF]
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Z. Zhu, W. Jiang, H. E. Ganther, and H. J. Thompson Mechanisms of Cell Cycle Arrest by Methylseleninic Acid Cancer Res., January 1, 2002; 62(1): 156 - 164. [Abstract] [Full Text] [PDF]
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L. Rao, B. Puschner, and T. A. Prolla Gene Expression Profiling of Low Selenium Status in the Mouse Intestine: Transcriptional Activation of Genes Linked to DNA Damage, Cell Cycle Control and Oxidative Stress J. Nutr., December 1, 2001; 131(12): 3175 - 3181. [Abstract] [Full Text] [PDF]
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Z. Wang, C. Jiang, H. Ganther, and J. Lu Antimitogenic and Proapoptotic Activities of Methylseleninic Acid in Vascular Endothelial Cells and Associated Effects on PI3K-AKT, ERK, JNK and p38 MAPK Signaling Cancer Res., October 1, 2001; 61(19): 7171 - 7178. [Abstract] [Full Text] [PDF]
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A. Ghose, J. Fleming, K. El-Bayoumy, and P. R. Harrison Enhanced Sensitivity of Human Oral Carcinomas to Induction of Apoptosis by Selenium Compounds: Involvement of Mitogen-activated Protein Kinase and Fas Pathways Cancer Res., October 1, 2001; 61(20): 7479 - 7487. [Abstract] [Full Text] [PDF]
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Y. Dong, D. Lisk, E. Block, and C. Ip Characterization of the Biological Activity of {{gamma}}-Glutamyl-Se- methylselenocysteine: A Novel, Naturally Occurring Anticancer Agent from Garlic Cancer Res., April 1, 2001; 61(7): 2923 - 2928. [Abstract] [Full Text]
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C. Jiang, Z. Wang, H. Ganther, and J. Lu Caspases as Key Executors of Methyl Selenium-induced Apoptosis (Anoikis) of DU-145 Prostate Cancer Cells Cancer Res., April 1, 2001; 61(7): 3062 - 3070. [Abstract] [Full Text]
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H. E. Ganther and C. Ip Thioredoxin Reductase Activity in Rat Liver Is Not Affected by Supranutritional Levels of Monomethylated Selenium In Vivo and Is Inhibited Only by High Levels of Selenium In Vitro J. Nutr., February 1, 2001; 131(2): 301 - 304. [Abstract] [Full Text]
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D. G. Menter, A. L. Sabichi, and S. M. Lippman Selenium Effects on Prostate Cell Growth Cancer Epidemiol. Biomarkers Prev., November 1, 2000; 9(11): 1171 - 1182. [Abstract] [Full Text]
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S. D. Mark, Y.-L. Qiao, S. M. Dawsey, Y.-P. Wu, H. Katki, E. W. Gunter, J. F. Fraumeni Jr., W. J. Blot, Z.-W. Dong, and P. R. Taylor Prospective Study of Serum Selenium Levels and Incident Esophageal and Gastric Cancers J Natl Cancer Inst, November 1, 2000; 92(21): 1753 - 1763. [Abstract] [Full Text] [PDF]
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 M. M. van Bakel, G. Printzen, B. Wermuth, and U. N Wiesmann Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients Am. J. Clinical Nutrition, October 1, 2000; 72(4): 976 - 981. [Abstract] [Full Text] [PDF]
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C. Ip, H. J. Thompson, Z. Zhu, and H. E. Ganther In Vitro and in Vivo Studies of Methylseleninic Acid: Evidence That a Monomethylated Selenium Metabolite Is Critical for Cancer Chemoprevention Cancer Res., June 1, 2000; 60(11): 2882 - 2886. [Abstract] [Full Text] [PDF]
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C. Ip, H. J. Thompson, and H. E. Ganther Selenium Modulation of Cell Proliferation and Cell Cycle Biomarkers in Normal and Premalignant Cells of the Rat Mammary Gland Cancer Epidemiol. Biomarkers Prev., January 1, 2000; 9(1): 49 - 54. [Abstract] [Full Text]
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M. Janghorbani, Y. Xia, P. Ha, P. D. Whanger, J. A. Butler, J. W. Olesik, and L. Daniels Metabolism of Selenite in Men with Widely Varying Selenium Status J. Am. Coll. Nutr., October 1, 1999; 18(5): 462 - 469. [Abstract] [Full Text] [PDF]
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H. E. Ganther Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase Carcinogenesis, September 1, 1999; 20(9): 1657 - 1666. [Abstract] [Full Text] [PDF]
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