Tamoxifen

Tamoxifen is a medication most commonly prescribed against breast cancer. Tamoxifen works by blocking the action of the hormone estrogen in the body; since most breast cancers rely on estrogen in order to live and grow, once estrogen is no longer present, they gradually lose their ability to reproduce and die. The drug is essential for any woman at high risk for breast cancer as well as any who has undergone the disease, because it exerts protective properties on cells and reduces the risk of the cancer returning. Tamoxifen usage is associated with positive side effects, such as a reduced risk for developing osteoporosis and heart disease; however, negative side effects have been reported also. All of them are mild to moderate and include hot flashes, vaginal dryness and fatigue.

Lancet Oncol. 2005 May;6(5):295-300.
Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial.
Perdona S, Autorino R, De Placido S, D'Armiento M, Gallo A, Damiano R, Pingitore D, Gallo L, De Sio M, Bianco AR, Di Lorenzo G.
Department of Urology, National Tumour Institute, G Pascale Foundation IRCSS, Naples, Italy.

BACKGROUND: Gynaecomastia and breast pain are frequent adverse events with bicalutamide monotherapy, and might cause some patients to withdraw from treatment. We aimed to compare tamoxifen with radiotherapy for prevention and treatment of gynaecomastia, breast pain, or both during bicalutamide monotherapy for prostate cancer. METHODS: 51 patients were randomly assigned to 150 mg bicalutamide per day, 50 patients to 150 mg bicalutamide per day and to 10 mg tamoxifen per day for 24 weeks, and 50 patients to 150 mg bicalutamide per day and radiotherapy (one 12-Gy fraction on the day of starting bicalutamide). 35 of the 51 patients allocated bicalutamide alone developed gynaecomastia or breast pain and were subsequently randomly allocated to tamoxifen (n=17) or radiotherapy (n=18) soon after symptoms started (median 180 days, range 160-195). Gynaecomastia and breast pain were assessed once a month. Severity of gynaecomastia was scored on the basis of the largest diameter. Breast pain was scored as none, mild, moderate, or severe. The primary outcome was frequency of gynaecomastia or breast pain; secondary outcomes were safety and tolerability, relapse-free survival, as assessed by concentration of prostate specific antigen, and quality of life. Analyses were by intention to treat. RESULTS: 35 of 51 patients assigned bicalutamide alone developed gynaecomastia, compared with four of 50 assigned bicalutamide and tamoxifen (odds ratio [OR] 0.1 [95% CI 0.08-0.12], p=0.0009), and with 17 of 50 assigned bicalutamide and radiotherapy (0.51 [0.47-0.54], p=0.008). Breast pain was seen in 29 of 51 patients allocated bicalutamide alone, compared with three allocated bicalutamide and tamoxifen (0.1 [0.07-0.11], p=0.009), and with 15 allocated bicalutamide and radiotherapy (0.43 [0.40-0.45], p=0.02) In 35 patients assigned bicalutamide alone who subsequently developed gynaecomastia, breast pain, or both, tamoxifen significantly reduced the frequency of gynaecomastia (0.2 [0.18-0.22], p=0.02). INTERPRETATION: Antioestrogen treatment with tamoxifen could help patients with prostate cancer to tolerate the hypergonadotropic effects of bicalutamide monotherapy.

Arq Bras Endocrinol Metabol. 2004 Dec;48(6):903-8. Epub 2005 Mar 8.
[Use of tamoxifen in the treatment of Riedel's thyroiditis: report of a case.]
[Article in Portuguese]
Iwakura MS, Fontes R.
Instituto Estadual de Diabetes e Endocrinologia, Rio de Janeiro, RJ.

Treatment of Riedel's thyroiditis (RT) consists of surgery in cases of local limited fibrosis. In most cases, however, it is required the use of anti-inflammatory agents like glucocorticoids or, in those who fail to respond or relapse, tamoxifen can be useful. We report a case of RT in a 55-year-old black woman associated with hypothyroidism and hypoparathyroidism. We evaluated the treatment with tamoxifen, 20mg twice a day, for eleven months. After sixty days of therapy, patient had no compressive symptoms previously presented. However, in a follow-up of eleven months, there was little objective improvement by regular ultrasonography and computed tomography of the cervical region. Tamoxifen can be useful in RT, mainly when glucocorticoids are not indicated. The ideal duration of this therapy remains to be established.

Int J Oncol. 2005 Apr;26(4):1025-31.
Rationale for sequential tamoxifen and anticancer drugs in adjuvant setting for patients with node- and receptor-positive breast cancer.
Kim R, Tanabe K, Emi M, Uchida Y, Osaki A, Toge T.
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan. rkim@hiroshima-u.ac.jp.

Since the survival benefit of tamoxifen (TAM) combined with anticancer drugs in treating node- and receptor-positive breast cancer is small, appropriate treatment schedules and the rationale for the combination remains unclear. We examined the effect of estradiol (E2) on sensitivity to anticancer drugs to clarify the survival benefit of tamoxifen combined with anticancer drugs. We used the MTT assay to assess the effect of E2 on sensitivity to anticancer drugs in the E2 receptor-positive and -negative breast cancer cell lines, MCF-7 and MDA-MB-231, respectively. We assessed the expression of apoptosis-related proteins by Western blotting, and evaluated apoptosis using the TUNEL method. Serum levels of E2 were measured using an enzyme-labeled radioimmunoassay in patients with premenopausal breast cancer before and during treatment with tamoxifen. Estrogen administration decreased sensitivity in MCF-7 cells to the anticancer drugs, adriamycin (ADM), mitomycin C (MMC), and paclitaxel (TXL), evaluated as increases in the IC50 values for ADM (4.1-fold), MMC (1.9-fold) and TXL (13.0-fold), compared with those of each drug alone. Estradiol in MDA-MB-231 cells similarly increased the IC50 values for ADM (9.5-fold), MMC (15.6-fold), and TXL (2.4-fold). The decreased sensitivity to these anticancer drugs was associated with the attenuation of apoptosis. Estrogen dose-dependently increased the expression of Bcl-2 protein in MCF-7, but not in MDA-MB-231 cells, and suppressed the expression of Bax and cytochrome c induced by anticancer drugs in association with decreased apoptosis compared with the effect of each drug alone. Phosphorylation of the Bcl-2 protein induced by TXL was decreased in the presence of E2 in MCF-7 cells. Serum levels of E2 were increased in 5 patients without amenorrhea and in 1 patient with amenorrhea after treatment with TAM alone in adjuvant therapy, compared with levels before treatment. Estradiol decreased sensitivity to ADM, MMC, and TXL in MCF-7 and MDA-MB-231 breast cancer cells, and this was associated in part with an increase in the amount of Bcl-2 protein, and decreases in levels of Bax and cytochrome c leading to apoptosis. These results suggest that therapy with TAM and anticancer drugs should be sequentially scheduled with anticancer drugs followed by TAM in an adjuvant setting to treat patients with breast cancer for a potentially improved survival benefit.

Int J Cancer. 2004 Nov 10;112(3):357.
Prevention of breast cancer in women who carry BRCA1 or BRCA2 mutations: A critical review of the literature.
Calderon-Margalit R, Paltiel O.
Hadassah-Hebrew University Braun School of Public Health and Community Medicine, Jerusalem, Israel.
The purpose of our study was to review the evidence for the efficacy of surveillance for early detection, bilateral prophylactic mastectomy, prophylactic oophorectomy and chemoprevention in preventing breast cancer and improving survival of BRCA1 or BRCA2 carriers. A critical review of journal articles published between 1998 and 2004 identified by searches of MEDLINE, PubMed and references of retrieved articles was undertaken. None of the current evidence is based on randomized studies. The efficacy of surveillance for early detection of breast cancer among BRCA1 or BRCA2 carriers is not yet established. Screening with clinical breast examination and mammography showed lower sensitivity in BRCA1 or BRCA2 carriers than in the general population. Screening with MRI might offer higher sensitivity rates than mammography. Prophylactic mastectomy was shown to significantly reduce the risk of breast cancer by 89.5-100%. However, of all strategies reviewed, mastectomy was the least acceptable to women at high risk. Tamoxifen use was associated with breast cancer prevention among BRCA2 carriers (RR=0.38, 95%CI: 0.06-1.56). In BRCA1 or BRCA2 carriers with breast cancer, tamoxifen use was associated with the prevention of secondary breast cancer (OR= 0.50, 95% CI: 0.28-0.89). Prophylactic oophorectomy was associated with hazard ratios for breast cancer of 0.47 (95%CI:0.29-0.77) and 0.32 (95%CI: 0.08-1.20), in retrospective and short follow-up prospective cohort studies, respectively. There is a pressing need for more studies in order to determine which of the 4 strategies alone, or in combination, is the most effective for the prevention of breast cancer and for the improvement of survival of BRCA mutation carriers. Copyright 2004 Wiley-Liss, Inc.

Cardiovasc Res. 2004 Nov 1;64(2):346-355.
Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin.
Suarez Y, Fernandez C, Gomez-Coronado D, Ferruelo AJ, Davalos A, Martinez-Botas J, Lasuncion MA.
Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Ctra. de Colmenar, km 9, E-28034 Madrid, Spain.
OBJECTIVE: To study the mechanism involved in the cholesterol-lowering activity of tamoxifen, an estrogen receptor (ER) modulator widely used in breast cancer therapy. METHODS AND RESULTS: We used MOLT-4 cells, which do not express estrogen receptors and require important amounts of cholesterol for proliferation. We firstly confirmed that tamoxifen reduced cholesterol biosynthesis by inhibiting sterol Delta(8,7)-isomerase and Delta(24)-reductase activities, which resulted in the accumulation of zymosterol. In cells incubated in the presence of low-density lipoprotein (LDL) (120 μg cholesterol/ml), tamoxifen stimulated LDL receptor activity and expression in a dose-dependent manner, as determined by 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-labeled LDL uptake, LDL receptor expression on the cell surface and LDL receptor mRNA levels. Furthermore, tamoxifen, but not lovastatin, inhibited the egress of LDL-derived cholesterol from lysosomes, as ascertained by filipin staining in both MOLT-4 and HepG2 cells. When studied in combination, especially at relatively high LDL concentrations in the medium, tamoxifen and lovastatin stimulated LDL receptor activity synergistically, which is attributed to the different mechanism of action these drugs exhibit. CONCLUSIONS: The present study demonstrates the stimulation of the LDL receptor by tamoxifen. These results explain the long-known hypolipidemic effect of tamoxifen and support its use, or that of other intracellular cholesterol trafficking inhibitors, in combination with statins for the reduction of plasma LDL cholesterol levels.

Endocrinology. 2004 Nov;145(11):5021-5032. Epub 2004 Jul 15.
Estrogen Modulates Microglial Inflammatory Mediator Production via Interactions with Estrogen Receptor {beta}
Baker AE, Brautigam VM, Watters JJ.
Department of Comparative Biosciences, 2015 Linden Drive, Madison, Wisconsin 53706. jjwatters@wisc.edu.
Estrogens are well known to exert antiinflammatory effects outside the central nervous system (CNS). They have also been shown to exert neuroprotective effects in the CNS after several types of injury, including neurodegeneration. However, the molecular mechanisms by which these effects occur remain unclear. Because microglial hyperactivation and their production of neurotoxins is associated with many types of brain injury for which estrogens are beneficial, we sought to investigate the ability of estrogen to modulate microglial function. Furthermore, because little is known regarding the role of each of the two known estrogen receptors (ERs) in microglia, our studies were designed to test the hypothesis that 17beta-estradiol (E(2)) exerts antiinflammatory effects in microglia, specifically via interactions with ERbeta. We tested this hypothesis using the murine microglial cell line BV-2, which naturally expresses only ERbeta. Our results indicate that not only does E(2) decrease lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, it also reduces the expression of cyclooxygenase-2, a target for estrogen that has not previously been reported for ERbeta. We also observed that LPS-stimulated TNFalpha mRNA was increased by estrogen. E(2) exerts these effects within 30 min compared with typical estrogen transcriptional responses. Tamoxifen and ICI 182,780 differentially blocked the inhibitory effects of E(2) on LPS-stimulated iNOS and cyclooxygenase-2. In addition, we show that E(2) alters LPS-stimulated MAPK pathway activation, supporting the idea that alterations in the MAPKs may be a potential mechanism by which ERbeta mediates decreased microglial activation.

Int J Biochem Cell Biol. 2004 Nov;36(11):2112-9.
Endocrine approaches for the treatment of early and advanced breast cancer in postmenopausal women.
Tobias JS.
Meyerstein Institute of Clinical Oncology, Middlesex Hospital, London W1T 3AA, UK. j.tobias@uclh.org
Preventing clinical progression is the major treatment goal for both early and advanced breast cancer. For hormone-responsive cases (about 70% of the total), this can necessitate the use of sequential hormone therapies at various points during the patient's life. Newer hormonal therapies, such as the third-generation aromatase inhibitor anastrozole, are now competing with tamoxifen as first choice endocrine therapy in breast cancer. In addition, a further non-steroidal aromatase inhibitor letrozole has been shown to be beneficial when given at completion of 5 years adjuvant tamoxifen. In light of these new data, current treatment paradigms need to be reviewed. Already well established as second-line treatments for advanced breast cancer, the improved risk:benefit profiles of anastrozole and letrozole compared with tamoxifen mean that these agents are now also recognised alternative treatments in the first-line relapse setting. More recent studies demonstrate that anastrozole may also have an improved risk:benefit profile compared with tamoxifen when used as initial adjuvant therapy in early breast cancer. Anastrozole is also being evaluated as a preventative treatment in women at high risk of developing breast cancer. A new addition to the endocrine treatment armamentarium is the oestrogen receptor antagonist fulvestrant, which, unlike tamoxifen, has no agonist effects. Fulvestrant is at least as effective as anastrozole in the second-line treatment of advanced breast cancer, and provides similar benefits to tamoxifen when used as first-line therapy in patients with advanced, hormone receptor-positive tumours.

J Neurobiol. 2004 Nov;61(2):209-21.
Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: Differences with the effect of estradiol.
Ciriza I, Carrero P, Azcoitia I, Lundeen SG, Garcia-Segura LM.
Instituto Cajal, C.S.I.C., E-28002 Madrid, Spain.
Neuroprotective effects of estradiol are well characterized in animal experimental models. However, in humans, the outcome of estrogen treatment for cognitive function and neurological diseases is very controversial. Selective estrogen receptor modulators (SERMs) may represent an alternative to estrogen for the treatment or the prevention of neurodegenerative disorders. SERMs interact with the estrogen receptors and have tissue-specific effects distinct from those of estradiol, acting as estrogen agonists in some tissues and as antagonists in others. In this study we have assessed the effect of tamoxifen, raloxifene, lasofoxifene (CP-336,156), bazedoxifene (TSE-424), and 17beta-estradiol on the hippocampus of adult ovariectomized rats, after the administration of the excitotoxin kainic acid. Administration of kainic acid induced the expression of vimentin in reactive astroglia and a significant neuronal loss in the hilus. SERMs did not affect vimentin immunoreactivity in the hilus, while 17beta-estradiol significantly reduced the surface density of vimentin immunoreactive profiles. Estradiol, tamoxifen (0.4-2 mg/kg), raloxifene (0.4-2 mg/kg), and bazedoxifene (2 mg/kg) prevented neuronal loss in the hilus after the administration of kainic acid. Lasofoxifene (0.4-2 mg/kg) was not neuroprotective. These findings indicate that SERMs present different dose-dependent neuroprotective effects. Furthermore, the mechanisms of neuroprotection by SERMs and estradiol are not identical, because SERMs do not significantly affect reactive gliosis while neuroprotection by estradiol is associated with a strong down-regulation of reactive astroglia. (c) 2004 Wiley Periodicals, Inc. J Neurobiol, 2004.

Oncol Rep. 2004 Nov;12(5):1109-14.
Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid.
Vogt U, Bielawski KP, Bosse U, Schlotter CM.
European Laboratory Association, Section IbbenbYren, 49477 IbbenbYren, Germany. druvogt@eurolabass.de.
Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.

Reprod Toxicol. 2004 Nov;19(1):79-86.
Estrogenic and toxic effects of polychlorinated biphenyls on cultured ovarian germ cells of embryonic chickens.
Xie M, Zhang C.
Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, No. 268 Kaixuan Road, Hangzhou 310029, PR China.
Polychlorinated biphenyls (PCBs) are man-made ubiquitous pollutants that have detrimental effects on reproduction and endocrine functions in a variety of species. In the present study, estrogenic and toxic effects of PCBs on embryonic chicken ovarian development were evaluated by a germ-somatic cell co-culture system. Ovarian cells were cultured in serum-free medium and challenged with a mixture of PCBs (Aroclor 1254). Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release. Results showed that lower PCBs (0.1-1microg/ml) manifested mainly estrogenic effect to stimulate germ cell proliferation, while higher PCBs (10microg/ml) imposed severe toxicity on germ and somatic cells. The toxic effect of PCBs could be attenuated by an antioxidant tocopherol. PCBs induced condensed nuclear chromosome in ovarian cells and caused cell exfoliation and breakdown within initial hours of treatment. After 24h, the estrogenic effect of PCBs began to exhibit and the survived germ cells manifested proliferation. Inhibition of the estrogenic effect of PCBs by tamoxifen led to increased toxicity on germ cells and somatic cells. These results indicate that PCBs exposure may interfere with ovarian germ cell proliferation and cause reproductive disorder via both toxic and estrogenic actions in embryonic chickens.

Mol Cell Endocrinol. 2004 Oct 29;226(1-2):33-42.
Intracellular signaling involved in estrogen regulation of serotonin reuptake.
Koldzic-Zivanovic N, Seitz PK, Watson CS, Cunningham KA, Thomas ML.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031, USA.
17beta-Estradiol (E(2)) regulates neuronal activity via genomic and rapid, non-genomic mechanisms. The rat serotonergic neuronal cell line (RN46A) was used to investigate the rapid effects of E(2) on serotonin (5-HT) reuptake and on potential intracellular signaling pathways. RN46A cells express the serotonin transporter (SERT) and estrogen receptor (ER)beta, but not ERalpha. Fifteen minute E(2) treatment (10(-9)M) decreased 5-HT uptake. Intracellular cAMP levels were not increased by 15min E(2) treatment; however, E(2) caused an increase in intracellular Ca(2+) levels, with a maximum response within the first minute. The response was E(2) specific, since other steroids (17alpha-estradiol, testosterone, and progesterone) had no effect. The ER antagonist ICI 182,780 blocked the rapid E(2) effects on intracellular Ca(2+) levels as did the selective ER modulator tamoxifen. In summary, changes in intracellular Ca(2+) levels caused by E(2) and mediated through ERbeta may be responsible for observed rapid effects of E(2) on SERT activity.

J Clin Oncol. 2004 Oct 15;22(20):4067-74.
Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy.
Low JA, Berman AW, Steinberg SM, Danforth DN, Lippman ME, Swain SM.
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bldg 8, Rm 5101, 8901 Wisconsin Ave, Bethesda, MD 20889-5015; e-mail: swains@mail.nih.gov.
PURPOSE To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. Results OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.

Sci Total Environ. 2004 Oct 15;333(1-3):167-84.
Investigating the environmental transport of human pharmaceuticals to streams in the United Kingdom.
Ashton D, Hilton M, Thomas KV.
Environment Agency, National Centre for Ecotoxicology and Hazardous Substances, Evenlode House, Howbery Park, Wallingford, Oxon, OX10 8BD, UK.
The occurrence of 12 selected pharmaceutical compounds and pharmaceutical compound metabolites in sewage treatment works (STW) effluents and surface waters was investigated. The substances selected for the monitoring programme were identified by a risk ranking procedure to identify those substances with the greatest potential to pose a risk to the aquatic environment. STW final effluent and surface water samples were collected from Corby, Great Billing, East Hyde, Harpenden and Ryemeads STWs. Ten of the 12 pharmaceutical compounds were detected in the STW effluent samples: propranolol (100%, median=76 ng/l), diclofenac (86%, median=424 ng/l), ibuprofen (84%, median=3086 ng/l), mefenamic acid (81%, median=133 ng/l), dextropropoxyphene (74%, median=195 ng/l), trimethoprim (65%, 70 ng/l), erythromycin (44%, <10 ng/l), acetyl-sulfamethoxazole (33%, median=<50 ng/l), sulfamethoxazole (9%, median=<50 ng/l), tamoxifen (4%, median=<10 ng/l). In the corresponding receiving streams, fewer compounds and lower concentrations were found: propranolol (87%, median=29 ng/l), ibuprofen (69%, median=826 ng/l), mefenamic acid (60%, median=62 ng/l), dextropropoxyphene (53%, median=58 ng/l), diclofenac (47%, median=<20 ng/l), erythromycin (38%, median=<10 ng/l), trimethoprim (38%, median=<10 ng/l), acetyl sulfamethoxazole (38%, median=<50 ng/l). Four human pharmaceutical compounds were detected in samples upstream of the STWs sampled: ibuprofen (57%, median=181 ng/l), trimethoprim (36%, median <10 ng/l), erythromycin (17%, median=<10 ng/l), propranolol (14%, median=<10 ng/l), suggesting that longer range stream transport of some compounds is possible. The particular STW that was sampled and the month that it was sampled significantly influenced the measured concentrations of several, but not all, substances. There was no significant relationship between usage data and the overall frequency with which different substances were detected. There was however, some evidence to suggest that usage data are positively associated with concentrations of pharmaceuticals in effluent and, particularly, with concentrations measured in surface waters below STWs. These results suggest that most sewage treatment works in England and Wales are likely to be routinely discharging small quantities of pharmaceuticals into UK rivers. None of the pharmaceuticals were found at concentrations that were high enough to cause acute toxic impacts to aquatic organisms. However, insufficient data were available to be able to comment on whether the concentrations measured have the potential to result in more subtle long-term effects on aquatic organisms (e.g. effects on growth, ability to reproduce).

Oncogene. 2004 Oct 14;23(47):7810-20.
Effects of a conditionally active v-ErbB and an EGF-R inhibitor on transformation of NIH-3T3 cells and abrogation of cytokine dependency of hematopoietic cells.
McCubrey JA, Shelton JG, Steelman LS, Franklin RA, Sreevalsan T, McMahon M.
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA. mccubreyj@mail.ecu.edu
Epidermal growth factor (EGF) and its cognate receptor (EGF-R) are often dysregulated in human neoplasia. Moreover, EGF-R-transformed cell lines have constitutive EGF-R activity, which makes elucidation of its effects difficult to determine. In the following studies, the effects of a novel conditionally activated form of EGF-R, v-ErbB:ER, on the morphological transformation of NIH-3T3 cells and the abrogation of hematopoietic cell cytokine dependence were investigated. The v-ErbB ES-4 oncogene was fused to the hormone binding domain of the estrogen receptor (ER). This construct, v-ErbB:ER, requires beta-estradiol or 4-OH tamoxifen for activation. v-ErbB:ER conditionally transformed NIH-3T3 cells and abrogated cytokine dependence of hematopoietic cells. Stimulation of v-ErbB:ER activity resulted in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK/ERK kinase cascades. To determine the importance of these signal transduction pathways, the conditionally transformed hematopoietic cells were treated with EGF-R, PI3K and MEK inhibitors. The EGF-R inhibitor AG1478 effectively inhibited MEK, ERK and Akt activation, and induced apoptosis when the cells were grown in response to v-ErbB:ER. Apoptosis was observed at 100- to 1000-fold lower concentrations of AG1478 when the cells were grown in response to v-ErbB:ER as opposed to IL-3. Furthermore, the parental, BCR-ABL- and Raf-transformed cells were only susceptible to the apoptosis-inducing effects of AG1478 at the highest concentrations demonstrating the specificity of these inhibitors. MEK or PI3K inhibitors suppressed ERK or Akt activation, respectively, and induced apoptosis in the v-ErbB:ER-responsive cells. However, MEK and PI3K inhibitors only induced apoptosis at 1000-fold higher concentrations than the EGFR inhibitor. This novel v-ErbB:ER construct and these conditionally transformed cell lines will be useful to further elucidate ErbB-mediated signal transduction and to determine the effectiveness of various inhibitors in targeting different aspects of EGF-R-mediated signal transduction and malignant transformation.

Neurology. 2004 Oct 12;63(7):1230-3.
Risk of ischemic stroke with tamoxifen treatment for breast cancer: a meta-analysis.
Bushnell CD, Goldstein LB.
Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710, USA. Cheryl.Bushnell@duke.edu
OBJECTIVE: To assess the overall risk of stroke, specifically ischemic stroke, associated with tamoxifen use by performing a meta-analysis of data reported in breast cancer trials. BACKGROUND: Tamoxifen increases the risk of venous thromboembolism in women with breast cancer, but its relationship to stroke risk is uncertain. METHODS: A systematic review of randomized controlled trials of tamoxifen for breast cancer management and prevention published since 1980 was performed using MEDLINE. The summary odds ratio (OR) and 95% CI were calculated using the Mantel-Haenszel method, followed by a statistical test for heterogeneity. RESULTS: Nine trials met the inclusion criteria, and six trials specified ischemic stroke outcomes. The Mantel-Haenszel summary OR was 1.82 (95% CI, 1.41 to 2.36) for ischemic stroke and 1.40 (1.14 to 1.72) for any stroke. The chi2 heterogeneity test was 6.0 (p > 0.1) for ischemic stroke and 16.1 (p < 0.05) for any stroke. The random-effects summary OR of Der Simonian and Laird for any stroke was 1.29 (0.92 to 1.81). During a mean follow-up period of 4.9 years, the frequency of ischemic stroke was 0.71% with tamoxifen vs 0.39% for controls (absolute increased risk, 0.32%; number needed to harm [NNH], 313). CONCLUSIONS: Women with breast cancer who were treated with tamoxifen had an 82% increased risk of ischemic stroke and a 29% increased risk of any stroke, but the absolute risk is small. Further studies assessing prespecified cerebrovascular outcomes are ongoing and will further clarify the risk of stroke associated with tamoxifen use.

Biochem Biophys Res Commun. 2004 Oct 8;323(1):332-8.
SRA coactivation of estrogen receptor-alpha is phosphorylation-independent, and enhances 4-hydroxytamoxifen agonist activity.
Coleman KM, Lam V, Jaber BM, Lanz RB, Smith CL.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3498, USA.
The ability of steroid receptor RNA activator (SRA), an AF-1 coactivator, to contribute to differences in estrogen receptor (ER)-alpha and ERbeta transcriptional activity was tested. In transient transfections, SRA expression increased ERalpha- and ERbeta-dependent gene expression. However, when the receptors' amino-terminal A/B regions were examined as GAL4 DNA binding domain fusions, SRA enhanced the activity of GAL-ABalpha but not GAL-ABbeta. Exogenous SRA also enhanced AF-2 activity for both receptors, indicating that SRA effects are not limited to AF-1. Simultaneously mutating three phosphorylation sites within GAL-ABalpha domain only modestly reduced SRA coactivation of GAL-ABalpha, suggesting that phosphorylation does not play a major role in SRA function relative to this domain. SRA enhanced ERalpha activity stimulated by 4-hydroxytamoxifen, but was unable to convert this mixed antiestrogen to an ERbeta agonist. Thus, SRA is an ERalpha AF-1-specific coactivator that enhances the agonist activity of tamoxifen-bound ERalpha and may contribute to tamoxifen resistance. Copyright 2004 Elsevier Inc.

Br J Cancer. 2004 Oct 4;91(7):1251-60.
Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients.
Azria D, Gourgou S, Sozzi WJ, Zouhair A, Mirimanoff RO, Kramar A, Lemanski C, Dubois JB, Romieu G, Pelegrin A, Ozsahin M.
[1] 1Department of Radiation Oncology, Centre Regional de Lutte contre le Cancer, Rue Croix Verte, 34298 Montpellier, France [2] 2EMI 0227, Centre Regional de Lutte contre le Cancer, Rue Croix Verte, 34298 Montpellier, France.
Concomitant use of adjuvant tamoxifen (TAM) and radiation therapy (RT) is not widely accepted. We aim to assess whether this treatment is associated with an increased risk of developing subcutaneous fibrosis after conservative or radical surgery in breast cancer patients. We analysed 147 women with breast cancer treated with adjuvant RT, and who were included in the KFS 00539-9-1997/SKL 00778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects. TAM (20 mg day(-1)) with concomitant RT was prescribed in 90 hormone receptor-positive patients. There was a statistically significant difference in terms of complication-relapse-free survival (CRFS) rates at 3 years, 48% (95% CI 37.2-57.6%) vs 66% (95% CI 49.9-78.6%) and complication-free survival (CFS) rates at 2 years, 51% (95% CI 40-61%) vs 80% (95% CI 67-89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8 radiation-induced apoptosis, 20% (95% CI 10-31.9%), 66% (95% CI 51.1-77.6%), and 79% (95% CI 55-90.9%) for CD8 24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis; therefore, caution is needed for radiosensitive patients.British Journal of Cancer (2004) 91, 1251-1260. doi:10.1038/sj.bjc.6602146 www.bjcancer.com Published online 24 August 2004

Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L774-83. Epub 2004 Jun 04.
Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms.
Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ.
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. l.donnelly@imperial.ac.uk
Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic stilbene found in the skins of red fruits, including grapes, that may be responsible for some of the health benefits ascribed to consumption of red wine. Resveratrol has been shown to have antioxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited IL-8 and granulocyte-macrophage colony-stimulating factor release from A549 cells. Neither the estrogen receptor antagonist tamoxifen nor the glucocorticoid antagonist mifepristone altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Resveratrol and quercetin inhibited NF-kappaB-, activator protein-1-, and cAMP response element binding protein-dependent transcription to a greater extent than the glucocorticosteroid dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production (IC50 = 3.6 +/- 2.9 microM) in human primary airway epithelial cells. Resveratrol also inhibited granulocyte-macrophage colony-stimulating factor release (IC50 = 0.44 +/- 0.17 microM), IL-8 release (IC50 = 4.7 +/- 3.3 microM), and cyclooxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel nonsteroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases.

Am J Surg. 2004 Oct;188(4):426-8.
Understanding the biologic mechanisms responsible for breast-cancer progression during tamoxifen or fulvestrant treatment.
Hardin C, Pommier R, Lefleur B, Jackson T, Toth-Fejel S.
Division of Surgical Oncology, Department of General Surgery, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., I.223A, Portland, OR 97201-3098, USA.
BACKGROUND: Dehydroepiandosterone sulfate (DHEAS) causes breast-cancer proliferation, even during tamoxifen or fulvestrant blockade. The purpose of this study was to determine possible mechanisms for this treatment failure. METHODS: T-47D cells (estrogen receptor [ER] and progesterone receptor [PR] positive) were treated with fulvestrant (10 micromol/L), tamoxifen (10 mmol/L or 0.0001 nmol/L), or vehicle and stimulated with DHEAS. Gene expression of ER, PR, insulin-like growth factor (IGF)-1 and -2, and insulin-like growth-factor binding protein (IGFBP)-1 through -4 was determined. RESULTS: ER and PR gene expression decreased by 1.3- and 4-fold with fulvestrant and DHEAS. ER expression decreased by 2.7-fold with 0.0001 nmol/L tamoxifen and DHEAS. ER and PR expression were unchanged by 10 nmol/L tamoxifen. IGF-1 and IGF-2 were not expressed. IGFBP-2 and -4 expression decreased by 1.9- and 1.6-fold after DHEAS stimulus, although this was not statistically significant. CONCLUSIONS: DHEAS exposure, even in the presence of tamoxifen and fulvestrant, induces changes in ER and PR gene expression that may be partially responsible for breast cancer progression.

Anticancer Drugs. 2004 Oct;15(9):889-897.
Tamoxifen and epigallocatechin gallate are synergistically cytotoxic to MDA-MB-231 human breast cancer cells.
Chisholm K, Bray BJ, Rosengren RJ.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
High concentrations of specific catechins [epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG)] inhibit the proliferation of many different cancer cell lines. The aim of this work was to determine if low concentrations of catechins with and without 4-hydroxytamoxifen (4-OHT) co-treatment would cause significant cytotoxicity in estrogen receptor-positive (ERα) and -negative (ERα) human breast cancer cells. Therefore, MCF-7, T47D, MDA-MB-231 and HS578T cells were incubated with EGCG, EGC or ECG (5â€"25 microM) individually and in combination with 4-OHT for 7 days. Cell number was determined by the sulforhodamine B cell proliferation assay. As single agents, none of the catechins were cytotoxic to T47D cells, while only EGCG (20 microM) elicited cytotoxicity in MCF-7 cells. Additionally, no benefit was gained by combination treatment with 4-OHT. ERα human breast cancer cells were more susceptible as all three catechins were significantly cytotoxic to HS578T cells at concentrations of 10 microM. In this cell line, combination with 4-OHT did not increase cytotoxicity. However, the most striking results were produced in MDA-MB-231 cells. In this cell line, EGCG (25 microM) produced a greater cytotoxic effect than 4-OHT (1 microM) and the combination of the two resulted in synergistic cytotoxicity. In conclusion, low concentrations of catechins are cytotoxic to ERα human breast cancer cells, and the combination of EGCG and 4-OHT elicits synergistic cytotoxicity in MDA-MB-231 cells.

Biopharm Drug Dispos. 2004 Oct;25(7):283.
Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A.
Bekaii-Saab TS, Perloff MD, Weemhoff JL, Greenblatt DJ, von Moltke LL.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA.
The effects of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen on transport attributable to P-glycoprotein were studied using Caco-2 cell monolayers in a transwell system, with rhodamine-123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal-apical and apical-basal directions in Caco-2 monolayers. The mean IC(50) values for inhibition of rhodamine-123 transport were: 29 microM for tamoxifen; 26 microM for N-desmethyltamoxifen; and 7.4 microM for 4-hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (+/-SE) IC(50) values versus formation of alpha-hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (+/-3.9) and 18.4 (+/-5.3) microM for tamoxifen; 10.2 (+/-1.7) and 9.2 (+/-1.5) microM for N-desmethyltamoxifen; and 2.6 (+/-0.5) and 2.7 (+/-0.3) microM for 4-hydroxytamoxifen. Thus, tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, do not appear to be substrates for transport by P-glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P-glycoprotein as well as CYP3A-mediated metabolism. Inhibitory effects of the principal metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies. Copyright (c) 2004 John Wiley & Sons, Ltd.

J Clin Endocrinol Metab. 2004 Jan;89(1):375-83.
Differential Recruitment of Coregulator Proteins Steroid Receptor Coactivator-1 and Silencing Mediator for Retinoid and Thyroid Receptors to the Estrogen Receptor-Estrogen Response Element by beta-Estradiol and 4-Hydroxytamoxifen in Human Breast Cancer.
Fleming FJ, Hill AD, McDermott EW, O'Higgins NJ, Young LS.
Department of Surgery (F.J.F., A.D.K.H., E.W.M., N.J.O., L.S.Y.), St. Vincent's University Hospital, and Conway Institute of Biomolecular and Biomedical Research (A.D.K.H., L.S.Y.), University College Dublin, Dublin 4, Ireland.
Estrogen receptor (ER)-alpha and ER-beta function as transcription factors, and both interact with nuclear regulatory proteins to enhance or inhibit transcription. We hypothesized that coregulators are expressed in breast cancer and may be differentially recruited by ERs in the presence of estrogen and tamoxifen. ER-beta was found to be expressed more frequently in node-negative patients (P < 0.05). Expression of steroid receptor coactivator-1 (SRC-1) was associated with nodal positivity (P < 0.05) and resistance to endocrine treatment (P < 0.001). The spatial coexpression of ER-alpha, ER-beta, and the coregulatory proteins was established using immunofluorescence. In both cell lines (MCF-7 and T47D) and in primary breast cancer cell cultures, beta-estradiol up-regulated ER-beta and coregulator protein expression and increased ER-alpha/ER-beta interaction with the estrogen response element (ERE). 4- Hydroxy-tamoxifen (4-OHT) increased ER-alpha and silencing mediator for retinoid and thyroid receptors (SMRT) expression and increased ER-ERE binding. SRC-1 and SMRT were identified at the ER-ERE complex, and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation. Both ER-alpha and ER-beta preferentially bound SRC-1 in the presence of beta-estradiol. Conversely, in cells treated with 4-OHT, ER-alpha and ER-beta bound SMRT. Differential recruitment of SRC-1 and SMRT by ER-alpha and ER-beta in the presence of beta-estradiol and 4-OHT may be central to the response of the tumor to endocrine treatment

Pediatr Hematol Oncol. 2003 Sep;20(6):473-6.
Encouraging result of tamoxifen in a retinoblastoma patient with central nervous system metastasis.
Tacyildiz N, Yavuz G, Unal E, Gunduz K, Gunalp I, Ekinci C.
Department of Pediatric Oncology, Ankara University Medical School, Ankara, Turkey.
Extraocular retinoblastoma occurs more frequently in developing countries as a delayed diagnosis and prognosis of patients with conventional therapy is very poor. Metastatic retinoblastoma, especially in the central nervous system (CNS), is a highly lethal disease. Tamoxifen has been used in some previous studies with variety of responses to therapy in patients with unresectable recurrent brain tumors. A 7-year-old girl with recurrent metastatic retinoblastoma received 60 mg/m2 tamoxifen in addition to chemotherapy and CNS radiotherapy. She was in remission until she has died in a traffic accident at week 114. The authors think that tamoxifen can be added to treatment protocols of metastatic retinoblastoma to provide longer and at least higher quality of life for these patients.

Biomed Pharmacother. 2003 Dec;57(10):447-51.
Estrogen/EGF receptor interactions in breast cancer: rationale for new therapeutic combination strategies.
Lichtner RB.
Belzigerstrasse 39, 10823, Berlin, Germany
In the therapy of estrogen receptor (ER) positive human mammary carcinomas, the treatment with the antiestrogen tamoxifen has been well established. However, the development of hormone resistance is an important factor in breast cancer progression against endocrine therapy. The presence of the receptor for EGF (EGFR) correlates with lack of response towards antiestrogen therapy. The EGFR is not only involved in tumor cell growth, survival signaling, cell migration, metastasis formation and angiogenesis, but also seems to confer reduced responses of tumor cells towards anti-hormones. Concomitant inhibition of both, the receptors for estrogen and EGF may be necessary to improve breast cancer therapy.

Int J Fertil Womens Med. 2003 Sep-Oct;48(5):217-25.
Treatment of ductal carcinoma in situ of the breast: review of recent advances and future prospects.
Mokbel K.
Brunel Institute of Cancer Genetics, and Breast & Endocrine Surgeon, St. George's Hospital, London, UK.
Ductal carcinoma in situ (DCIS) is a heterogeneous disease characterized by noninvasive clonal proliferation of malignant epithelial cells arising from the mammary ducts and terminal ductal-lobular units. Its reported incidence is rising due to the wide adoption of screening mammography. The combination of nuclear grade and presence of necrosis is currently the best predictor of biological behavior. Approximately 25-50% of DCIS lesions progress to invasive disease if left untreated. The treatment options for DCIS include total mastectomy with or without immediate breast reconstruction (IBR), local excision (LE) plus adjuvant radiotherapy (RT), and LE alone. Total mastectomy is associated with lowest rates of local recurrence and breast cancer-specific mortality. If IBR is considered, then skin-sparing mastectomy (SSM) combined with autologous myocutaneous flap reconstruction can achieve excellent cosmesis without compromising local control. The role of adjuvant radiotherapy (RT) after LE remains controversial. Three recent randomized controlled trials have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However, these trials did not identify any subgroups of patients where RT could be safely omitted and were criticized for lack of emphasis on standardized and meticulous tissue processing and pathological evaluation. Retrospective studies indicate that RT can be safely omitted after adequate LE (margin width > or = 1 cm) of small (< 15 mm), non-high grade DCIS not associated with necrosis. The role of tamoxifen in the treatment of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS; however, the potential role of the sentinel node biopsy (SNB) in selected high-risk cases requires further evaluation. Areas of ongoing and future research include the potential role of third-generation aromatase inhibitors and third- and fourth-generation selective estrogen receptor modulators in women with hormone-sensitive DCIS; the potential role of cyclo-oxygenase type 2 inhibitors in DCIS treatment and prevention; the value of magnetic resonance and nuclear medicine imaging; and the clinical relevance of gene expression profiling, proteomics, radiofrequency or LASER ablation and mammary ductoscopy in the management of DCIS.

Neo adjuvant Tamoxifen in post menopausal patients with operable breast cancer.
Salmon RJ, Remvikos Y, Campana F, Languille O, Magdalenat H, Asselain B, Clough KB, The Breast Group of the Institut Curie.
The Breast Group, Institut Curie, 26 rue d'Ulm, 75005, Paris, France
AIMS: Tamoxifen is widely used as adjuvant therapy in receptor positive post menopausal breast cancer. Little is known about its efficacy as neo adjuvant therapy in terms of breast conservation and improved survival.METHODS: We analyzed the tumour response to 20-30 mg Tamoxifen for 6 months in post menopausal patients with oestrogen receptor positive tumours. Treatment included Tamoxifen for 6 months, surgical resection, and irradiation for post menopausal patients refusing initial mastectomy; aged>/=70 years; or with other factors delaying surgery.RESULTS: Between April 1994 and June 1998, 102 patients, age 73+/-87 (54-90) were studied. There were 24 T1, 56 T2, 14 T3, and 8 T4 tumours. Clinical response to Tamoxifen was observed in all patients, with a median size reduction from 31+/-15 (9-70) to 16+/-9 mm (0-50), 15 clinical and 6 complete responses. 88/102 patients were treated conservatively. Radiotherapy was given to 80 and a flash technique to 8 patients. All patients but one are still alive.CONCLUSION: Neo adjuvant Tamoxifen in operable post menopausal ER positive breast cancer is associated with a good clinical response rate and facilitates conservative surgery. Tamoxifen has a valuable role as neo-adjuvant treatment in terms of breast conservation and survival.