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At least 19 recordsLinked to original sources
PubMedDate not supplied

Inhibition of vascular endothelial cells by 1,4-phenylenebis (methylene)selenocyanate--a novel chemopreventive organoselenium compound.

Organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) was investigated for its effects on endothelial cell proliferation in vitro and angiogenesis in vivo. The organoselenium compound, p-XSC, has been shown to prevent carcinogen-induced tumorigenesis in murine model systems with low toxicity. Since tumor growth and metastasis are dependent on angiogenesis, we investigated the effects of the organoselenium compound on this process. Human umbilical vein endothelial cells treated with p-XSC showed concentration dependent inhibition of protein synthesis and cell viability in vitro with a TCID50 value of 6 microM. Subsequently, we studied the effects of p-XSC on experimental angiogenesis. Addition of p-XSC to three-dimensional cultures inhibited endothelial cell tube formation. Furthermore, p-XSC treatment inhibited growth factor induced angiogenesis in chick chorioallantoic membrane assays and i.p. administration of p-XSC inhibited neovascularization induced by tumor cells implanted subcutaneously into athymic mice. These studies suggest that vascular endothelium is an additional target for the chemopreventive organoselenium compound p-XSC.

Animals↗
PubMed1997

Inhibition of human cytochrome P450-catalyzed oxidations of xenobiotics and procarcinogens by synthetic organoselenium compounds.

The effects of synthetic chemopreventive organoselenium compounds 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate (o-, m-, and p-XSC, respectively), benzyl selenocyanate (BSC), and dibenzyl diselenide (DDS) and inorganic sodium selenite on the oxidation of xenobiotics and procarcinogens by human cytochrome P450 (P450 or CYP) enzymes were determined in vitro. Spectral studies showed that BSC and three XSC compounds (but not sodium selenite or DDS) induced type II difference spectrum when added to the suspension of liver microsomes isolated from beta-naphthoflavone-treated rats, with m-XSC being the most potent in inducing spectral interactions with P450 enzymes; m-XSC also produced a type II spectral change with human liver microsomes. o-, m-, and p-XSC inhibited 7-ethoxyresorufin O-deethylation catalyzed by human liver microsomes when added at concentrations below 1 microM levels, but BSC and DDS were less effective. All of these compounds inhibited the oxidation of model substrates for human P450s to varying extents. We studied the effects of these compounds on the activation of procarcinogens by recombinant human CYP1A1, 1A2, and 1B1 enzymes using Salmonella typhimurium NM2009 tester strain for the detection of DNA damage. The three XSCs were found to be very potent inhibitors of metabolic activation of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, and 2-aminoanthracene, catalyzed by CYP1A1, 1A2, and 1B1, respectively. The potency of inhibition of m-XSC on CYP1B1-dependent activation of 2-aminoanthracene was compatible to those of alpha-naphthoflavone. These inhibitory actions may, in part, account for the mechanisms responsible for cancer prevention by organoselenium compounds in laboratory animals.

Animals↗
PubMed2001

Chemoprevention of colon cancer by a glutathione conjugate of 1,4-phenylenebis(methylene)selenocyanate, a novel organoselenium compound with low toxicity.

We have consistently shown that several synthetic Organoselenium compounds are superior cancer chemopreventive agents and less toxic than selenite or certain naturally occurring selenoamino acids. 1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is the lead Organoselenium compound in that it has been shown to be the most effective and the least toxic agent in several experimental cancer models. It is not known whether p-XSC or one of its metabolites is responsible for its chemopreventive efficacy. As an initial step, we synthesized one of its putative metabolites, i.e., the glutathione conjugate of p-XSC (p-XSe-SG), and determined its stability in the pH range from 2 to 8 and in the diet under normal feeding conditions. We also assessed its maximum tolerated dose and examined its chemopreventive efficacy against azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. p-XSe-SG proved to be very stable over the pH range tested. The maximum tolerated dose of p-XSe-SG determined in a 6-week subchronic toxicity study was found to be >210 ppm (>40 ppm selenium) when the compound was added to AIN-76A high-fat diet. To assess the efficacy of this agent in the postinitiation period of colon carcinogenesis, male F344 rats 6 weeks of age were fed the high-fat diet, and at beginning of weeks 7 and 8, all of the rats intended for carcinogen treatment were given AOM at a dose of 15 mg/kg body weight by s.c. injection. Two days after the carcinogen treatment, the groups of rats consuming the high-fat control diet began their respective high-fat experimental diet regimens with 0, 56, or 84 ppm p-XSe-SG (0.1, 10, and 15 ppm of selenium) supplementation. All animals continued on their respective diets for 38 weeks after the AOM-treatment and were then killed. Colon tumors were evaluated histologically using routine procedures and were also analyzed for cyclooxygenase (COX)-1 and COX-2 expression and enzymatic activities. The results indicate that p-XSeSG administered during the post-initiation stage significantly inhibited both the incidence (P < 0.05-0.01) and the multiplicity (P < 0.05-0.005) of AOM-induced colon adenocarcinomas. This agent also greatly suppressed the multiplicity (P < 0.01-0.001) of AOM-induced exophytic adenocarcinomas in a dose-dependent manner. Feeding of 56 or 84 ppm p-XSe-SG in the diet significantly suppressed total COX activity (P < 0.02 to -0.01) and COX-2 specific activity (P < 0.005-0.0005) but had minimal effect on the protein expression levels of COX-1 and COX-2. These results suggest that the newly developed synthetic Organoselenium compound, p-XSe-SG, is stable in the diet and at wide pH ranges, inhibits colon carcinogenesis when administered during the postinitiation stage, and inhibits COX activity. Compared with previous efficacy studies and considering the toxicity associated with selenium, p-XSe-SG seems to be the least toxic Organoselenium chemopreventive agent thus far tested in the experimental colon carcinogenesis. Studies are in progress to delineate whether p-XSe-SG is also effective when administered during the progression stage of colon carcinogenesis.

Animals↗
PubMed1989

Chemoprevention of experimental mammary carcinogenesis by the synthetic organoselenium compound, benzylselenocyanate, in rats.

The effect of the dietary organoselenium compound, benzylselenocyanate (BSC) along with its sulphur analogue, benzylthiocynanate (BTC) and sodium selenite (Na2SeO3), on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis was examined in female Sprague-Dawley rats during the initiation phase of carcinogenesis. Semipurified diets containing 25 p.p.m. of BSC and 25 p.p.m. BTC, and 4 p.p.m. Selenium as Na2SeO3 in drinking water were given to 5-week-old rats for 3 weeks starting 2 weeks before, during and until 1 week after carcinogen treatment. At 7 weeks of age animals were given a single dose of DMBA (10 mg) in 1 ml olive oil by oral intubation. One week after DMBA treatment, the groups receiving BSC- and BTC-supplemented diets were transferred to the unsupplemented standard diets and the group of rats receiving Na2SeO3 in drinking water was transferred to regular tap water for the duration of the experiment. The results indicate that the rats receiving BSC in their diet showed a highly significant inhibition of tumor incidence and tumor multiplicity as well as a prolonged latency period when compared to the group fed the control diet. Neither BTC nor Na2SeO3 had any effect on the subsequent development of mammary tumors. These results indicate that dietary BSC inhibits mammary tumor incidence during the initiation phase of carcinogenesis and is a considerably more potent inhibitor than its sulphur analogue BTC and inorganic selenium. This is the first report that demonstrates the inhibition of mammary carcinogenesis by a synthetic organoselenium compound.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors and DNA adduct formation in the mammary glands of female Sprague-Dawley rats by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.

We synthesized a novel organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (XSC), possessing low toxicity by comparison with inorganic Na2SeO3, and several other synthetic organoselenium compounds (K. El-Bayoumy, Cancer Res., 45: 3631-3636, 1985). We tested the effect of XSC treatment during the initiation phase on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma formation. A semipurified high-fat diet containing 80 ppm of XSC (40 ppm as selenium) was fed to 6-wk-old virgin female Sprague-Dawley rats for 2 wk, starting 1 wk before and ending 1 wk after carcinogen treatment. At 7 wk of age, rats were given a single dose of DMBA (5 mg) in 0.2 ml of olive oil by gastric intubation; the experiment was terminated 16 wk later. The development of mammary tumors in those rats that received XSC-supplemented diets was significantly inhibited when compared with the control group (fed the same diet without XSC supplements). This was evident from tumor incidence (percentage of tumor-bearing rats, 88 versus 20) and multiplicity of tumors (mean number of tumors/rats, 3.96 versus 0.28). The finding that XSC acts as a chemopreventive agent in the DMBA mammary tumor model prompted us to examine the effect of dietary XSC on DMBA-DNA binding in both the liver and mammary tissue under conditions identical to those described above for the bioassay. Rats (four/group) were killed 6, 24, 48, and 168 h after [3H]DMBA (5 mg/rat; specific activity, 51.2 mCi/mM) administration. Liver and mammary tissue were obtained and DNA was isolated. Dietary XSC was found to inhibit total DMBA-DNA binding in the mammary tissue, but not in the liver. The most profound effect was observed at early time points, i.e., 24 to 48 h after [3H]DMBA administration. The inhibition in total binding was attributed to a reduction in the formation of the three major adducts derived from bay-region diol-epoxides of DMBA; these were identified as anti-diol-epoxide:deoxyguanosine, syn-diol-epoxide:deoxyadenosine, and anti-diol-epoxide:deoxyadenosine adducts on the basis of their chromatographic characteristics on high-pressure liquid chromatography and on a boronate affinity column. The inhibition of the DMBA-DNA binding in the target tissue provides a plausible explanation for the chemopreventive effect of XSC during the initiation stage of carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Evaluation of organoselenium compounds for potential chemopreventive properties in colon cancer.

Our previous studies have demonstrated that dietary benzylselenocyanate (BSC) and 1,4-phenylenebis (methylene) selenocyanate (p-XSC); organoselenium compounds, act as potential chemopreventive agents in colon carcinogenesis in F344 rats. As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium and BSC, we evaluated the positional isomers of BSC namely o-, m-, and p-methoxy BSC and dibenzyl diselenide (DDS) for their potential chemopreventive properties using colonic epithelial cell proliferation as an efficacy endpoint. p-XSC and inorganic selenium, which were found to inhibit colon carcinogenesis in earlier preclinical efficacy study, were included as positive controls. Male F344 rats were fed the control diet containing 8 ppm Na2SeO3 or 10 ppm of each o-, m-, and p-methoxy BSC and DDS equivalent to 4.1 ppm Se or 20 ppm p-XSC (10 ppm Se) 2 weeks prior to carcinogen (AOM, 15 mg/kg body wt., once weekly for 2 weeks) administration and during and until 8 weeks after AOM treatment. Vehicle-control animals received an equal volume of normal saline. One hour prior to sacrifice, all animals were injected with bromodeoxyuridine (BrdU, 20 mg/kg body wt.). Administration of o-, m-, and p-methoxy BSC, p-XSC, DDS, and Na2SeO3 resulted in decreased colonic labeling index in animal treated with AOM compared to control diet. Notably, p-XSC and Na2SeO3, which showed previously colon tumor inhibitory activity in preclinical efficacy study, were also effective in the present study. The results of our previous and current studies indicate that structurally modified synthetic organoselenium compounds may have great potential as chemopreventive agents.

Animals↗
PubMedDate not supplied

Chemoprevention of mammary cancer by diallyl selenide, a novel organoselenium compound.

Previous research has demonstrated that structurally distinctive organoselenium compounds are superior to the corresponding sulfur analogs in cancer prevention. The present study was designed to extend this observation to diallyl selenide (DASe), a volatile synthetic compound, and diallyl sulfide (DAS), a flavor component of garlic. Their anticarcinogenic activities were evaluated using the 7,12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumor model. Rats were gavaged three times with DASe (6 or 12 mumol/kg body wt) or DAS (300, 900 or 1,800 mumol/kg) at 96, 48 and 24 hours before DMBA treatment. Significant tumor inhibition was found with the two doses of DASe and the highest dose of DAS. Based on these results, DASe appears to be at least 300 times more active than DAS. Analysis of total DMBA-DNA binding and individual DNA adducts in the mammary gland and liver showed that DASe had no effect on these parameters, suggesting that DASe might influence some unknown risk-associated events other than carcinogen activation/detoxification. Although the mechanism of action of DASe remains to be elucidated, its potential relevance to natural products will be discussed in the context of the chemistry of selenium-enriched garlic which has been reported to be effective in cancer protection in several studies.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Induction of apoptosis in human gastric adenocarcinoma cells by two novel organoselenium compounds, TS-2 and TS-6.

Two new organoselenium compounds, 4-ethyl-4-hydroxy-2-p-tolyl-4H-5,6-dihydro-1,3-selenazine (TS-2) and 4-hydroxy-4-methyl-6-propyl-2-p-tolyl-4H-5,6-dihydro-1,3-selenazine++ + (TS-6) were investigated for their inhibitory effect on the growth of 8 human tumor cell lines, including stomach, lung, prostate and colon cancer cell lines, in vitro. Both TS-2 and TS-6 exhibited the strongest cytotoxicity against a gastric adenocarcinoma (TMK-1) among 8 human tumor cell lines, and their IC50 were 2.38 microM and 2.78 microM, respectively. Twenty-four-h exposure of TMK-1 cells to TS-2 or TS-6 (0.1-100 microM) in the absence of serum led to a concentration-dependent increase of cytotoxicity. Exposure of TMK-1 cells to TS-2 or TS-6 (5, 10 or 20 microM) in the presence of 5% serum resulted in significant inhibition of TMK-1 cell proliferation in a concentration- and time-dependent manner. Morphological changes including shrinkage of the nucleus, and DNA ladder fragmentation, which are considered to be the typical features of apoptosis, were observed in TMK-1 cells in response to TS-2 or TS-6. Furthermore, the caspase-3 activity in TMK-1 cells treated with TS-2 or TS-6 was also found to be increased in a time-dependent manner, in parallel with the induction of DNA fragmentation. Taken together, the results of the present study suggest that the inhibition of growth of TMK-1 cells by TS-2 and TS-6 is mediated by the induction of apoptosis.

Adenocarcinoma↗
PubMed2001

Self-Assembled Monolayers of Organoselenium Compounds on Gold: Surface-Enhanced Raman Scattering Study.

To understand the binding nature of organoselenium compounds on gold, we have examined the adsorption behavior of several representative organoselenium compounds, i.e., benzeneselenol (BSe), diphenyl diselenide, dibenzyl diselenide, dioctyl diselenide, and benzyl phenyl selenide (BPSe) on the Au surface by virtue of surface-enhanced Raman spectroscopy (SERS). BSe chemisorbs on gold as selenolate with a tilted orientation. Upon adsorption, the Se-Se bonds of diselenides are cleaved to form selenolates, analogous to the formation of thiolate monolayers from disulfides. BPSe adsorbs on gold without any C-Se bond scission. The benzyl moiety of BPSe assumes a rather vertical stance while the phenyl moiety is more tilted to the gold surface. Copyright 2001 Academic Press.

Journal Article↗
PubMed2000

Effect of three diaryl tellurides, and an organoselenium compound in trout erythrocytes exposed to oxidative stress in vitro.

Previous literature reports have demonstrated that nucleated trout erythrocytes in conditions of oxidative stress are subjected to DNA and membrane damage, and inactivation of glutathione peroxidase. The present study was undertaken to evaluate the ability of three diaryl tellurides and the organoselenium compound ebselen to protect trout (Salmo irideus) erythrocytes against oxidative stress, induced thermally and by a variation of pH. The antioxidant ability of these molecules was evaluated through chemiluminescence. Impairment of DNA was assessed using the comet assay, a rapid and sensitive single cell gel electrophoresis technique, used to detect primary DNA damage in individual cells. At low concentrations (<10 microM), all the compounds used presented a protective effect on DNA damage without altering the hemolysis rate. In higher concentrations, they accelerated the hemolysis rate and two of the diaryl tellurides were strongly genotoxic.

Animals↗
PubMed1994

Inhibition of thymidine kinase in cultured mammary tumor cells by the chemopreventive organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.

To identify mechanisms by which the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) mediates its chemopreventive activities, we have examined its effects on cell lines derived from breast cancer of humans and rats. When log-phase cells were treated with a dose of 1 microM p-XSC, we observed a significant decrease in thymidine kinase (TK) activity within 4 h, and reduced thymidine incorporation after 24-48 h. When the dose of p-XSC was increased to 2 microM, the decrease in TK was accompanied by a modest, but significant, decrease in thymidine incorporation at 4 h, and a greater inhibition after 24-48 h. At a dose of > or = 3 microM, we observed a large decrease in TK, accompanied by > 70% reduction in thymidine incorporation, as well as decreases in mitochondrial activity and cell numbers, all within 4 h. Equal concentrations of selenium in the form of Na2SeO3 had no effect on the parameters described above. These data suggest that inhibition of thymidine kinase is an early effect of p-XSC in cultured breast tumor cells.

Adenosine Triphosphate↗
PubMed2000

Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung carcinogens present in tobacco smoke. A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 micromol/mouse) and NNK (3 micromol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks. Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after carcinogen administration. Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model. Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver. Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver. Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPX(Se)), GST-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver. These studies suggest that the chemopreventive efficacy of p-XSC, when fed during carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these carcinogens, and the induction of specific phase II enzymes involved in their detoxification. The mechanisms that account for the effect of p-XSC when fed after carcinogen administration remain to be determined.

Animals↗
PubMed1997

Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets.

BACKGROUND: Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued. PURPOSE: Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets. METHODS: Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically. RESULTS: No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet. CONCLUSIONS: In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.

Adenocarcinoma↗
PubMedDate not supplied

Evaluation of organoselenium compounds for potential chemopreventive properties in colon carcinogenesis.

As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium, we have evaluated benzyl selenocyanate (BSC) and its o-, m-, p-nitro and -methoxy isomers, o-, m-, and p-isomers of phenylenebis(methylene)selenocyanate (XSC), dibenzyl diselenide (DDS), and 2,2'-diselenobis[((N,N-dimethylamino)methyl)- benzene]bis(hydrochloride salt) (DSBDB) for their potential colon tumor inhibitory properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), a preneoplastic lesion, in male F344 rats prior to preclinical efficacy study. In the first experiment, the effect of these agents administered during initiation and postinitiation periods of carcinogenesis was investigated. Male F344 rats were fed diets containing 8 ppm Na2SeO3 or 10 ppm of each BSC and its analogues, DDS and DSBDB or 20 ppm of each XSC analogue, two weeks prior to AOM (15 mg/kg body wt., once weekly for two weeks, s.c.) administration and during and until 8 weeks after AOM treatment. Formalin-fixed and methylene blue stained colons were scored for AOM-induced ACF using the light microscope. Taking body weight gains and multiplicity of 4 or more AC/focus, the inhibitory effects of Na2SeO3, o-, m- and p-methoxy-BSC, p-XSC and DDS were much greater than those of the other selenium compounds. In the second study, the effects of these agents when administered during the initiation or postinitiation periods were investigated. The results indicated that o-, m-, and p-methoxy-BSC, DDS and p-XSC significantly inhibited crypt multiplicity during the initiation period whereas o-, and p-methoxy-BSC, p-XSC and DDS suppressed crypt multiplicity during the postinitiation period. It is concluded that o-, and p-methoxy-BSC, p-XSC and DDS possess potential chemopreventive properties in colon cancer. Further studies are warranted to evaluated these agents for chemopreventive properties in preclinical efficacy studies.

Animals↗
PubMed2000

Liquid chromatography/electrospray mass spectrometry of organoselenium compounds with postcolumn crown ether complexation.

Postcolumn addition is an effective means of alleviating or solving ionization-related problems in liquid chromatography/electrospray ionization mass spectrometry (LC/ESIMS). In the current study, initial attempts to develop a direct LC/ESIMS method for an organoselenium compound, 4-hydroxyphenyl 2-methyl-2-aminoethyl selenide (HOMePAESe), were unsuccessful because of extensive fragmentation which occurred even under the mildest in-source collision-induced dissociation (CID) conditions. To reduce the extent of compound fragmentation, a crown ether, 18-crown-6, was added postcolumn to the system, forming a complex with HOMePAESe, which survived the electrospray ionization process with reduced fragmentation and hence improved sensitivity for the major ions. The general applicability of this crown ether complexation approach to clinical samples was demonstrated by the analysis of HOMePAESe in human urine, using a structural analogue, 4-fluorophenyl 2-aminoethyl selenide (FPAESe) as an internal standard. The limit of detection for HOMePAESe, based on a signal-to-noise ratio of 3:1, was estimated to be 5 pg/microL in urine. The potential application of this approach to the general analysis of other amine-containing compounds was also evaluated.

Chromatography, Liquid↗
PubMed1995

Chemoprevention of cancer by organoselenium compounds.

A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short-term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long-term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4-phenylenebis(methylene)selenocyanate (p-XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p-XSC inhibited mammary tumor development induced by 7,12-dimethylbenz(a)anthracene (DMBA) during both the initiation and post-initiation phases of carcinogenesis in female CD rats. p-XSC inhibited DMBA-DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p-XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p-XSC was also shown to inhibit cell growth and induce a dose-dependent increase in cell death by apoptosis. In these assays p-XSC appears superior to selenite and to its sulfur analog, 1,4-phenylenebis(methylene)thiocyanate. Dietary p-XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Identification of volatile selenium compounds produced in the hydride generation system from organoselenium compounds.

We report a novel aqueous derivatization of selenomethionine (Semet), selenoethionine (Seet) and trimethylselenonium ion (TmSe) by NaBH4 and HCI to volatile selenium species, namely, diethyldiselenide (DeDSe), dimethyldiselenide (DMDSe), dimethylselenide (DmSe) and ethylhydrogenselenide (ESeH), in the hydride generation (HG) system. The volatile selenium compounds produced in the HG system were on-line trapped and concentrated in a U-tube that was immersed in the liquid nitrogen trap. The trapped volatile Se compounds were volatilized at 80 degrees C in a water bath, and 50-500 microL of volatile gas was injected into the GC/AED and GC/MS, respectively. It has been established that DmSe, DmDSe, and DeDSe are the predominant Se compounds that are produced in the HG system from TmSe, Semet, and Seet, respectively, followed by ESeH from Seet. Analytical methods previously employed have stated that these compounds are inactive in the HG system. Prior decomposition of Semet, Seet, and TmSe to selenous acid is essential before HG. To the best of our knowledge, current findings for the production and identification of volatile selenium compounds in the HG system are new and different from existing reports; hence, direct estimation of Semet, Seet, and TmSe is possible when coupling with a HG system using a suitable Se-specific detector.

Journal Article↗
PubMed1985

Effects of organoselenium compounds on induction of mouse forestomach tumors by benzo(a)pyrene.

The selenium analogues of three known inhibitors of chemical carcinogenesis were synthesized and the compounds were tested for their ability to inhibit the induction of forestomach tumors in mice by benzo(a)pyrene. Groups of female CD-1 mice were given NIH-07 diet, or NIH-07 diet to which one of the following test compounds had been added: p-methoxyphenol (30 mumol/g diet and 3.3 mumol/g diet); p-methoxybenzeneselenol (3.3 mumol/g diet); benzylthiocyanate (0.045 mumol/g diet); benzylselenocyanate (0.045 mumol/g diet); phenothiazine (3.8 mumol/g diet); and phenoselenazine (3.8 mumol/g diet). The test compounds were administered for 1 week prior to treatment with benzo(a)pyrene, during the 4 weeks of benzo(a)pyrene treatment, and for 1 week after benzo(a)pyrene treatment. Twelve weeks later the mice were sacrificed and forestomach tumors were counted and confirmed histologically as papillomas. p-Methoxyphenol was the most effective inhibitor and was the only one which significantly reduced both the percentage of tumor-bearing animals and the number of forestomach tumors per animal. At the 3.3-mumol/g diet, p-methoxyphenol reduced the number of tumors per animal from 3.3 to 0.8 (P less than 0.0003). p-Methoxybenzeneselenol reduced the number of tumors per animal from 3.3 to 2.0 (P less than 0.05). Benzylthiocyanate showed no significant inhibitory effect, but benzylselenocyanate reduced the number of tumors per animal from 3.3 to 1.7 (P less than 0.01). Phenothiazine significantly enhanced the number of tumors per animal from 3.3 to 6.5 (P less than 0.004). Phenoselenazine had no effect on tumor induction. The results of this study indicate that two synthetic organoselenium compounds, p-methoxybenzeneselenol and benzylselenocyanate, are effective inhibitors of mouse forestomach tumorigenesis induced by benzo(a)pyrene.

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