Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A randomized pilot trial was performed to evaluate the feasibility of administration of glutathione (GSH, 1200 mg, i.v.) as a protector in preventing diarrhea in patients operated on for endometrial cancer and submitted to adjuvant radiotherapy of the pelvis. Diarrhea occurred in 52% of patients in the untreated control group and only in 28% of patients in the GSH-treated group. Our preliminary data indicate that GSH administered before radiotherapy reduced the occurrence of diarrhea from oxidative damage to the intestinal mucosa. A large-scale phase III study is required to obtain definitive conclusions on the protective potential of GSH.
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PMID:Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomized trial in patients operated on for endometrial cancer. 129 31

The aim of this study was to determine whether glutathione peroxidase (GSH-Px) activity in endometrial tissue is regulated by sex hormones and to compare the GSH-Px activity of normal and cancerous endometrium. The localization of GSH-Px in human normal endometrium and endometrial cancer was determined immunohistochemically. GSH-Px activity was assayed in endometrial tissue obtained from women with endometrial cancer and age-matched controls, as well as in rat uterine tissue. GSH-Px immunoreactivity was localized in the glandular epithelium of normal human endometrium and reached a maximum in the late proliferative and early secretory phases of the menstrual cycle. In spayed rats, uterine GSH-Px activity was significantly increased by exogenous estrogen (P < 0.01) and significantly reduced by exogenous progesterone (P < 0.01). GSH-Px activity in endometrial cancer tissue was significantly higher (P < 0.01) than that in endometrial tissue from age-matched healthy controls. Among endometrial cancer tissues, a significant increase in GSH-Px activity was associated with well-differentiated rather than moderately or poorly differentiated adenocarcinoma (P < 0.01), with slight rather than marked myometrial invasion (P < 0.01), and with the presence of concurrent endometrial hyperplasia (P < 0.01). These results show that endometrial GSH-Px activity is regulated by sex hormones, being stimulated by estrogen and suppressed by progesterone, and that the level of GSH-Px activity in endometrial cancer tissue may be a significant prognostic factor.
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PMID:Glutathione peroxidase activity in endometrium: effects of sex hormones and cancer. 863 51

Tamoxifen is widely prescribed for the treatment of hormone-dependent breast cancer, and it has recently been approved by the Food and Drug Administration for the chemoprevention of this disease. However, long-term usage of tamoxifen has been linked to increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. The resulting quinone methide has the potential to alkylate DNA and may initiate the carcinogenic process. To further probe the chemical reactivity and toxicity of such an electrophilic species, we have prepared the 4-hydroxytamoxifen quinone methide chemically and enzymatically, examined its reactivity under physiological conditions, and quantified its reactivity with GSH. Interestingly, this quinone methide is unusually stable; its half-life under physiological conditions is approximately 3 h, and its half-life in the presence of GSH is approximately 4 min. The reaction between 4-hydroxytamoxifen quinone methide and GSH appears to be a reversible process because the quinone methide GSH conjugates slowly decompose over time, regenerating the quinone methide as indicated by LC/MS/MS data. The tamoxifen GSH conjugates were detected in microsomal incubations with 4-hydroxytamoxifen; however, none were observed in breast cancer cell lines (MCF-7) perhaps because very little quinone methides is formed. Toremifene, which is a chlorinated analogue of tamoxifen, undergoes similar oxidative metabolism to give 4-hydroxytoremifene, which is further oxidized to the corresponding quinone methide. The toremifene quinone methide has a half-life of approximately 1 h under physiological conditions, and its rate of reaction in the presence of excess GSH is approximately 6 min. More detailed analyses have indicated that the 4-hydroxytoremifene quinone methide reacts with two molecules of GSH and loses chlorine to give the corresponding di-GSH conjugates. The reaction mechanism likely involves an episulfonium ion intermediate which may contribute to the potential cytotoxic effects of toremifene. Similar to what was observed with 4-hydroxytamoxifen, 4-hydroxytoremifene was metabolized to di-GSH conjugates in microsomal incubations at about 3 times the rate of 4-hydroxytamoxifen, although no conjugates were detected with MCF-7 cells. Finally, these data suggest that quinone methide formation may not make a significant contribution to the cytotoxic and genotoxic effects of tamoxifen and toremifene.
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PMID:4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. 1064 66

Although tamoxifen is approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, several studies in animal models have shown that tamoxifen is heptocarcinogenic, and in humans, tamoxifen has been associated with an increased risk of endometrial cancer. One potential mechanism of tamoxifen carcinogenesis could involve metabolism of tamoxifen to 3,4-dihydroxytamoxifen followed by oxidation to a highly reactive o-quinone which has the potential to alkylate and/or oxidize cellular macromolecules in vivo. In the study presented here, we synthesized the 3,4-dihydroxytamoxifen, prepared its o-quinone chemically and enzymatically, and studied the reactivity of the o-quinone with GSH and deoxynucleosides. The E (trans) and Z (cis) isomers of 3,4-dihydroxytamoxifen were synthesized using a concise synthetic pathway (four steps). This approach is based on the McMurry reaction between the key 4-(2-chloroethoxy)-3,4-methylenedioxybenzophenone and propiophenone, followed by selective removal of the methylenedioxy ring of (E, Z)-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-(3, 4-methylenedioxyphenyl)-2-phenyl-1-butene with BCl(3). Oxidation of 3,4-dihydroxytamoxifen by activated silver oxide or tyrosinase gave 3,4-dihydroxytamoxifen-o-quinone as a mixture of E and Z isomers. The resulting o-quinone has a half-life of approximately 80 min under physiological conditions. Reaction of the o-quinone with GSH gave two di-GSH conjugates and three mono GSH conjugates. Incubation of 3,4-dihydroxytamoxifen with GSH in the presence of microsomal P450 gave the same GSH conjugates which were also detected in incubations with human breast cancer cells (MCF-7). Reaction of 3, 4-dihydroxytamoxifen-o-quinone with deoxynucleosides gave only thymidine and deoxyguanosine adducts; neither deoxyadenosine nor deoxycytosine adducts were detected. Preliminary studies conducted with human breast cancer cell lines showed that 3, 4-dihydroxytamoxifen exhibited cytotoxic potency similar to that of 4-hydroxytamoxifen and tamoxifen in an estrogen receptor negative (ER(-)) cell line (MDA-MB-231); however, in the ER(+) cell line (MCF-7), the catechol metabolite was about half as toxic as the other two compounds. Finally, in the presence of microsomes and GSH, 4-hydroxytamoxifen gave predominantly quinone methide GSH conjugates as reported in the previous paper in this issue [Fan, P. W., et al. (2000) Chem. Res. Toxicol. 13, XX-XX]. However, in the presence of tyrosinase and GSH, 4-hydroxytamoxifen was primarily converted to o-quinone GSH conjugates. These results suggest that the catechol metabolite of tamoxifen has the potential to cause cytotoxicity in vivo through formation of 3,4-dihydroxytamoxifen-o-quinone.
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PMID:Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4-dihydroxytamoxifen-o-quinone. 1064 67

Estrogen replacement therapy has been correlated with an increased risk of developing breast or endometrial cancer. 4-Hydroxyequilenin (4-OHEN) is a catechol metabolite of equilenin which is a minor component of the estrogen replacement formulation marketed under the name of Premarin (Wyeth-Ayerst). Previously, we showed that 4-OHEN autoxidizes to quinoids which can consume reducing equivalents and molecular oxygen, are potent cytotoxins, and cause a variety of damage to DNA, including formation of bulky stable adducts, apurinic sites, and oxidation of the phosphate-sugar backbone and purine/pyrimidine bases [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1127]. All of these deleterious effects could contribute to the cytotoxic and genotoxic effects of equilenin in vivo. In the study presented here, we examined the relative toxicity of 4-OHEN in estrogen receptor (ER) positive cells (MCF-7 and S30) compared to that in breast cancer cells without the estrogen receptor (MDA-MB-231). The data showed that 4-OHEN was 4-fold more toxic to MCF-7 cells (LC(50) = 6.0 +/- 0. 2 microM) and 6-fold more toxic to S30 cells (LC(50) = 4.0 +/- 0.1 microM) than to MDA-MB-231 cells (LC(50) = 24 +/- 0.3 microM). Using the single-cell gel electrophoresis assay (comet assay) to assess DNA damage, we found that 4-OHEN causes concentration-dependent DNA single-strand cleavage in all three cell lines, and this effect could be enhanced by agents which catalyze redox cycling (NADH) or deplete cellular GSH (diethyl maleate). In addition, the ER(+) cell lines (MCF-7 and S30) were considerably more sensitive to induction of DNA damage by 4-OHEN than the ER(-) cells (MDA-MB-231). 4-OHEN also caused a concentration-dependent increase in the amount of mutagenic lesion 8-oxo-dG in the S30 cells as determined by LC/MS-MS. Cell morphology assays showed that 4-OHEN induces apoptosis in these cell lines. As observed with the toxicity assay and the comet assay, the ER(+) cells were more sensitive to induction of apoptosis by 4-OHEN than MDA-MB-231 cells. Finally, the endogenous catechol estrogen metabolite 4-hydroxyestrone (4-OHE) was considerably less effective at inducing DNA damage and apoptosis in breast cancer cell lines than 4-OHEN. Our data suggest that the cytotoxic effects of 4-OHEN may be related to its ability to induce DNA damage and apoptosis in hormone sensitive cells in vivo, and these effects may be potentiated by the estrogen receptor.
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PMID:A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. 1081 50

Despite the beneficial effects of tamoxifen in the treatment and prevention of breast cancer, long-term usage of this popular antiestrogen has been linked to an increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. Alternatively, tamoxifen could undergo O-dealkylation to give cis/trans-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene, which is commonly known as metabolite E. Because of its structural similarity to 4-hydroxytamoxifen, metabolite E could also be biotransformed to a quinone methide, which has the potential to alkylate DNA and may contribute to the genotoxic effects of tamoxifen. To further probe the chemical reactivity/toxicity of such an electrophilic species, we have prepared metabolite E quinone methide chemically and enzymatically and examined its reactivity with glutathione (GSH) and DNA. Like 4-hydroxytamoxifen quinone methide, metabolite E quinone methide is quite stable; its half-life under physiological conditions is around 4 h, and its half-life in the presence of GSH is approximately 4 min. However, unlike the unstable GSH adducts of 4-hydroxytamoxifen quinone methide, metabolite E GSH adducts are stable enough to be isolated and characterized by NMR and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Reaction of metabolite E quinone methide with DNA generated exclusively deoxyguanosine adducts, which were characterized by LC/MS/MS. These data suggest that metabolite E has the potential to cause cytotoxicity/genotoxicity through the formation of a quinone methide.
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PMID:Bioactivation of tamoxifen to metabolite E quinone methide: reaction with glutathione and DNA. 1135 59

Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. However, tamoxifen has been shown to increase the risk of endometrial cancer which has stimulated research for new effective antiestrogens, such as droloxifene and toremifene. In this study, the potential for these compounds to cause cytotoxic effects was investigated. One potential cytotoxic mechanism could involve metabolism of droloxifene and toremifene to catechols, followed by oxidation to reactive o-quinones. Another cytotoxic pathway could involve the oxidation of 4-hydroxytoremifene to an electrophilic quinone methide. Comparison of the amounts of GSH conjugates formed from 4-hydroxytamoxifen, droloxifene, and 4-hydroxytoremifene suggested that 4-hydroxytoremifene is more effective at formation of a quinone methide. However, all three substrates formed similar amounts of o-quinones. Both the tamoxifen-o-quinone and toremifene-o-quinone reacted with deoxynucleosides to give corresponding adducts. However, the toremifene-o-quinone was shown to be considerably more reactive than the tamoxifen-o-quinone in terms of both kinetic data as well as the yield and type of deoxynucleoside adducts formed. Since thymidine formed the most abundant adducts with the toremifene-o-quinone, sufficient material was obtained for characterization by (1)H NMR, COSY-NMR, DEPT-NMR, and tandem mass spectrometry. Cytotoxicity studies with tamoxifen, droloxifene, 4-hydroxytamoxifen, 4-hydroxytoremifene, and their catechol metabolites were carried out in the human breast cancer cell lines S30 and MDA-MB-231. All of the metabolites tested showed cytotoxic effects that were similar to the parent antiestrogens which suggests that o-quinone formation from tamoxifen, droloxifene, and 4-hydroxytoremifene is unlikely to contribute to their cytotoxicity. However, the fact that the o-quinones formed adducts with deoxynucleosides in vitro implies that the o-quinone pathway might contribute to the genotoxicity of the antiestrogens in vivo.
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PMID:Synthesis and reactivity of potential toxic metabolites of tamoxifen analogues: droloxifene and toremifene o-quinones. 1174 47

Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4'-F-DMA, was synthesized. 4'-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4'-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4'-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4'-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.
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PMID:Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4'-fluoro substitution prevents quinoid formation. 1572 Jan 20

Although approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer in women. With an understanding of the potential carcinogenic mechanisms of these compounds, SERMs could in principle be designed or selected for use that avoids these problems. Acolbifene (EM-652) is a fourth-generation SERM and the active form of the ester prodrug EM-800. As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue. However, acolbifene was found in this investigation to form two kinds of quinone methides, either through chemical or through enzymatic oxidation. One was a classical acolbifene quinone methide, which was formed by oxidation at the C-17 methyl group, and the other was a diquinone methide involving the oxidation of two phenol groups. The half-life of the classical quinone methide was determined to be 32 +/- 0.4 s at physiological pH and temperature. The quinone methides reacted with glutathione (GSH) to form five mono-GSH conjugates and five di-GSH conjugates. The majority of GSH conjugates resulted from reaction of the classical acolbifene quinone methide with GSH. Incubations of acolbifene with GSH and either tyrosinase or human and rat liver microsomes also produced acolbifene quinone methide-GSH conjugates. In addition to reaction with GSH, the classical acolbifene quinone methide was also shown to react with deoxynucleosides. One of the major deoxynucleoside adducts was identified as the deoxyadenosine adduct resulting from reaction of the classical acolbifene quinone methide with the exocyclic amino group of adenine. Acolbifene could also induce DNA damage in the S30 breast cancer cell line. These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene.
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PMID:Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. 1572 Jan 21

Long-term usage of the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer. One potential mechanism of tamoxifen-induced carcinogenesis involves metabolism to reactive intermediates, such as an o-quinone, quinone methide, and carbocations. We have previously shown that the benzothiophene SERMs, raloxifene and desmethylated arzoxifene (DMA), can also be bioactivated to electrophilic quinoids by rat/human liver microsomes and rat hepatocytes [(2006) Chem. Res. Toxicol. 19, 1125-1137]. Because the uterus is a major target tissue of estrogens and antiestrogens, it was of interest to determine if quinoids could be formed from SERMs in uterine tissue potentially producing cytotoxic effects. Incubations with rat uterine microsomes showed that both raloxifene and DMA could be oxidized to electrophilic diquinone methides that were trapped as the corresponding GSH conjugates. A new raloxifene GSH-dependent conjugate was identified as raloxifene Cys-Gly that was formed from the hydrolysis of 7-glutathinyl raloxifene by gamma-glutamyl transpeptidase. Interestingly, the metabolism of raloxifene and DMA in rat uterine microsomes was not NADPH-dependent and could be inhibited by cyanide and NADPH or enhanced by H2O2. In addition, coincubations with the peroxidase substrates guaiacol or o-phenlyenediamine inhibited diquinone methide GSH conjugate formation from both SERMs. Incubations of raloxifene and DMA with horseradish peroxidase (HRP) were studied as models of the interaction between benzothiophene SERMs and peroxidase. The results showed that HRP could directly oxidize raloxifene and DMA to the corresponding dimers via the formation of phenoxyl radicals in the absence of exogenous hydrogen peroxide. In addition, GSH appears to be involved in multiple peroxidase-catalyzed oxidative metabolic pathways of benzothiophene SERMs. Finally, COATag (covert oxidatively activated tag) methodology, which involves the utilization of biotin-conjugated raloxifene and DMA, was used to identify target proteins by affinity chromatography. Incubations of raloxifene and DMA COATags with rat uterine microsomes showed several modified proteins by Western blot analysis. The protein modification could be enhanced by the addition of H2O2 and decreased by the addition of NADPH, suggesting that unlike liver metabolism the formation of quinoids in the uterus could be mediated by uterine peroxidases.
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PMID:Uterine peroxidase-catalyzed formation of diquinone methides from the selective estrogen receptor modulators raloxifene and desmethylated arzoxifene. 1763 Jul 9


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