Tamoxifen. Anti-Aging-Guide -- Your plan to stay young

Eur J Cancer. 2005 Mar;41(4):647-54. Epub 2005 Jan 18.
The soy isoflavone daidzein improves the capacity of tamoxifen to prevent mammary tumours.
Constantinou AI, White BE, Tonetti D, Yang Y, Liang W, Li W, van Breemen RB.
Department of Surgical Oncology, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.
The aim of this study was to determine how the efficacy of tamoxifen is affected when combined with soy isoflavones. To address this, female Sprague-Dawley rats were placed on diets supplemented with tamoxifen, genistein, daidzein, or a combination of each isoflavone with tamoxifen; a week later mammary tumours were induced by 7,12 dimethylbenzanthracene. The most effective diet was the tamoxifen/daidzein combination. It reduced tumour multiplicity by 76%, tumour incidence by 35%, tumour burden by over 95%, and increased tumour latency by 62% compared with positive controls. The tamoxifen/daidzein combination diet was in all aspects more effective while the tamoxifen/genistein combination was less effective than the tamoxifen diet. The tamoxifen/daidzein diet significantly decreased 8-oxo-deoxyguanosine levels (an indicator of oxidative DNA damage) in the mammary glands. This study conclusively shows for the first time the combination of daidzein with tamoxifen produces increased protection against mammary carcinogenesis, while the combination of genistein with tamoxifen produces an opposing effect when compared with tamoxifen alone.

Chem Biol Interact. 2004 Jul 20;148(3):149-61.
Protection of tamoxifen against oxidation of mitochondrial thiols and NAD(P)H underlying the permeability transition induced by prooxidants.
Cardoso CM, Almeida LM, Custodio JB.
Laboratorio de Bioquimica, Faculdade de Farmacia and Centro de Neurociencias de Coimbra, Universidade de Coimbra, Couraca dos Apostolos, 51, R/C, 3000-295 Coimbra, Portugal.
The effects of tamoxifen (TAM) were studied on the mitochondrial permeability transition (MPT) induced by the prooxidant tert-butyl hydroperoxide (t-BuOOH) or the thiol cross-linker phenylarsine oxide (PhAsO), in the presence of Ca(2+), in order to clarify the mechanisms involved in the MPT inhibition by this drug. The combination of Ca(2+) with t-BuOOH or PhAsO induces mitochondrial swelling and depolarization of membrane potential (DeltaPsi). These events are inhibited by cyclosporine A (CyA), suggesting the inhibition of the MPT. The pre-incubation of mitochondria with TAM also prevents those events and induces a time-dependent reversal of DeltaPsi depolarization following MPT induction, similarly to CyA. Moreover, TAM inhibits the Ca(2+) release and the oxidation of NAD(P)H and protein thiol (-SH) groups promoted by t-BuOOH plus Ca(2+). On the other hand, the MPT induced by PhAsO plus Ca(2+) does not induce -SH groups oxidation, supporting the notion that MPT induction by this compound is not mediated by the oxidation of specific membrane proteins groups. However, TAM also inhibits the PhAsO induced MPT, suggesting that this drug may inhibit this phenomenon by inhibiting PhAsO binding to -SH vicinal groups, implicated in the MPT induction. These data indicate that the MPT inhibition by TAM may be related to its antioxidant capacity in preventing the oxidation of NAD(P)H and -SH groups or by blocking these groups, since the oxidation of these groups increases the sensitivity of mitochondria to the MPT induction. Additionally, they suggest an MPT-independent pathway for TAM-induced apoptosis and a potential ER-independent mechanism for the effectiveness of this drug in the cancer therapy and prevention.

Anticancer Drugs. 2004 Aug;15(7):707-714.
Reduction of tamoxifen resistance in human breast carcinomas by tamoxifen-containing liposomes in vivo.
Zeisig R, Ruckerl D, Fichtner I.
Max-Delbruck-Center for Molecular Medicine, Department of Experimental Pharmacology, Berlin, Germany; Technical University of Berlin, Faculty III, Institute of Biotechnology, Berlin, Germany.
We investigated whether it is possible to reduce anti-estrogen resistance using liposomally encapsulated tamoxifen in vivo. Small liposomal vesicles containing up to 5.1 mg tamoxifen/ml liposomal suspension, together with an alkylphospholipid to enhance the cellular uptake, were prepared and characterized. Mice transplanted with different tumor models were treated with tamoxifen liposomes administered i.p. or orally as a bolus dose of 50 mg/kg once a week or as a daily dose of 10 mg/kg/day, both during a 4-week period. After orally administered tamoxifen liposomes, tumor growth was significantly reduced for the 3366/tamoxifen (acquired resistance) and for the MCF-7 (inherent resistance) models to 47 and 16%, respectively (treated to control value of relative tumor volume). Intraperitoneal treatment with tamoxifen liposomes revealed similar results. Investigation of biodistribution revealed especially an accumulation of liposomal tamoxifen in MCF-7 tumors and livers of the treated mice. These liposomes had uterotrophic properties comparable to the dissolved compound. This study demonstrates for the first time that a liposomal formulation of tamoxifen was able to induce pharmacological effects and to improve the therapeutic efficacy in several anti-estrogen-resistant xenografts.

Cochrane Database Syst Rev. 2004;(3):CD001024.
Tamoxifen for hepatocellular carcinoma.
Nowak A, Findlay M, Culjak G, Stockler M.
BACKGROUND: Hepatocellular carcinoma (primary liver cancer) is the third commonest cause of cancer mortality world-wide. Survival is poor for patients with advanced disease. Trials of tamoxifen for hepatocellular carcinoma have conflicting results. OBJECTIVES: To conduct a systematic review of the literature to assess the effect of tamoxifen on overall survival, quality-of-life, tumour response, and treatment toxicity in people with advanced hepatocellular carcinoma. SEARCH STRATEGY: We identified trials from The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2003), and MEDLINE database (1966 to November 2003). We searched bibliographies of review articles and identified trials, and hand-searched abstracts from relevant other meetings. SELECTION CRITERIA: All randomised clinical trials of treatment with tamoxifen compared to a control treatment without tamoxifen in people with hepatocellular carcinoma, including trials of tamoxifen versus placebo, tamoxifen versus best supportive care, and tamoxifen plus other treatment versus the same other treatment alone. DATA COLLECTION AND ANALYSIS: Three independent reviewers selected studies for inclusion, rated them for methodologic quality components (generation of allocation sequence; allocation concealment; blinding; and follow-up), and extracted data on the specified outcomes. Hazard ratios were derived for overall survival where possible. Meta-analysis was performed using a fixed-effect model. MAIN RESULTS: Ten randomised trials randomising 1709 patients were included. Tamoxifen versus placebo/no intervention had no significant effect on overall survival (hazard ratio 1.05; 95% CI 0.94 to 1.16; P = 0.4). This comparison showed no statistical heterogeneity (P = 0.2 and I(2 ) = 25.9%). Subgroup analysis showed that tamoxifen tended to increase mortality in trials with three adequate/three methodological components (hazard ratio 1.15; 95% CI 0.99 to 1.34; P = 0.06), showed no significant effect in trials with two adequate/three methodological components (hazard ratio 1.00; 95% CI 0.84 to 1.18; P = 0.98), and tended to reduce mortality in trials with one or less adequate/three methodological components (hazard ratio 0.82; 95% CI 0.60 to 1.12; P = 0.2), although this may have been confounded by the use of higher doses of tamoxifen in the better quality trials. Tamoxifen was associated with adverse effects. One trial measured patient quality of life, but the results were not reported in detail. REVIEWERS' CONCLUSIONS: These data do not support the use of tamoxifen for patients with hepatocellular carcinoma. Further research on the effects of tamoxifen in hepatocellular carcinoma does not seem warranted.

J Pediatr. 2004 Jul;145(1):71-6.
Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.
Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.
Department of Pediatrics, University of Ottawa, Ontario, Canada.
OBJECTIVES: To assess the efficacy of the anti-estrogens tamoxifen and raloxifen in the medical management of persistent pubertal gynecomastia. STUDY DESIGN: Retrospective chart review of 38 consecutive patients with persistent pubertal gynecomastia who presented to a pediatric endocrinology clinic. Patients received reassurance alone or a 3- to 9-month course of an estrogen receptor modifier (tamoxifen or raloxifene). RESULTS: Mean (SD) age of treated subjects was 14.6 (1.5) years with gynecomastia duration of 28.3 (16.4) months. Mean reduction in breast nodule diameter was 2.1 cm (95% CI 1.7, 2.7, P <.0001) after treatment with tamoxifen and 2.5 cm (95% CI 1.7, 3.3, P <.0001) with raloxifene. Some improvement was seen in 86% of patients receiving tamoxifen and in 91% receiving raloxifene, but a greater proportion had a significant decrease (>50%) with raloxifene (86%) than tamoxifen (41%). No side effects were seen in any patients. CONCLUSION: Inhibition of estrogen receptor action in the breast appears to be safe and effective in reducing persistent pubertal gynecomastia, with a better response to raloxifene than to tamoxifen. Further study is required to determine that this is truly a treatment effect.

Minerva Ginecol. 2003 Feb;55(1):87-93.
Effects of tamoxifen and estrogen replacement therapy on lipid metabolism and some other cardiovascular risk factors. A prospective study in hysterectomised women.
Imperato F, Marziani R, Perniola G, Ebano V, Fruscella M, Mossa B.
Dipartimento di Scienze Ginecologiche, Perinatologia e Puericultura, II Facolta di Medicina e Chirurgia, Universita degli Studi di Roma La Sapienza, Rome, Italy.
BACKGROUND: The aim of this clinical study was to evaluate the relationship of tamoxifen and the risk factors of cardiovascular disease in hysterectomised women. METHODS: Between 1992 and 1998, 93 women were recruited for a prospective study with follow-up at 0, 12 and 24 months. All women had an increased risk of breast cancer and they were hysterectomised and ovariectomised for a benign pathology. They were divided according to the following categories: Group A was constituted of 26 (28%) symptomatic patients (hot flushes, depression) who had received tamoxifen and oral conjugated estrogens. Group B was constituted of 27 (29%) symptomatic patients who had received tamoxifen and transdermal 17B-estradiol. Group C was constitued of 19 (21%) asymptomatic patients who had received only tamoxifen. Group D (control) was constitued of 21 (22%) asymptomatic patients who had not received any therapy. A venous blood sample for total cholesterol levels (T-C), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TRG), fibrinogen (FBR), platelets (PLT) and antithrombin III (AT III) was taken during follow-up. ANOVA (repeated measures) was used to assess statistical significance: p<0.05 was considered significant (95% CI). RESULTS: The patients who received tamoxifen with or without estrogen replacement therapy showed after 24 months, a reduction of T-C, LDL-C and FBR (p<0.01); the HDL-C levels did not vary significantly compared to the control group (p=NS); the 26 patients of group A showed an increase of HDL-C (p<0.02). We reported an increase of TRG in the patients of group A and C (p<0.05); on the contrary, we obtained a significant reduction of TRG (p<0.01) in the patients who received tamoxifen and transdermal 17B-estradiol (group B). There was no interaction on plateled count (p=NS). CONCLUSIONS: These results suggest the administration of tamoxifen in hysterectomised women with a high risk of breast cancer and without climateric symptoms. In these patients, tamoxifen could reduce coronary heart disease and incidence of breast cancer. The symptomatic patients are suggested to receive tamoxifen and transdermal 17B-estradiol because of the better effects on lipid metabolism.

J Natl Cancer Inst. 2003 Oct 1;95(19):1467-76.
Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer.
Dignam JJ, Wieand K, Johnson KA, Fisher B, Xu L, Mamounas EP.
Department of Health Studies and Cancer Research Center, The University of Chicago, Chicago, IL 60637, USA.
BACKGROUND: Obesity is associated with both increased breast cancer risk and poorer prognosis after disease onset. However, little is known about the effect of obesity on treatment efficacy. We evaluated the association of obesity with outcomes and with tamoxifen efficacy in women with early-stage, hormone-responsive breast cancer participating in a multicenter cancer cooperative group clinical trial. METHODS: The cohort consisted of 3385 women enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-14, a randomized, placebo-controlled trial evaluating tamoxifen for lymph node-negative, estrogen receptor (ER)-positive breast cancer. Hazards of breast cancer recurrence, contralateral breast tumors, other new primary cancers, and several mortality endpoints were evaluated in relation to body mass index (BMI), using statistical modeling to adjust for other prognostic factors. Median follow-up time was 166 months. All statistical tests were two-sided. RESULTS: The hazard of breast cancer recurrence was the same among obese (BMI > or =30.0 kg/m2) women as compared with underweight and normal-weight women (BMI <25.0; hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.80 to 1.18). Contralateral breast cancer hazard was higher in obese women than in underweight/normal-weight women (HR = 1.58, 95% CI = 1.10 to 2.25), as was the risk of other primary cancers (HR = 1.62, 95% CI = 1.16 to 2.24). Compared with normal-weight women, obese women had greater all-cause mortality (HR = 1.31, 95% CI = 1.12 to 1.54) and greater risk of deaths due to causes unrelated to breast cancer (HR = 1.49, 95% CI = 1.15 to 1.92). Breast cancer mortality was not statistically significantly increased for obese women (HR = 1.20, 95% CI = 0.97 to 1.49). Tamoxifen reduced breast cancer recurrence and mortality, regardless of BMI. CONCLUSIONS: For women with lymph node-negative, ER-positive breast cancer, obesity was not associated with a material increase in recurrence risk or a change in tamoxifen efficacy. However, because obesity was associated with increased risks of contralateral breast cancer, of other primary cancers, and of overall mortality, it may influence long-term outcomes for breast cancer survivors.

Cancer. 2003 Oct 1;98(7):1355-61.
Use of tamoxifen in the treatment of malignant melanoma.
Lens MB, Reiman T, Husain AF.University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

BACKGROUND: Tamoxifen has been used in the treatment of patients with metastatic malignant melanoma either as a single agent or, more commonly, in combination with other chemotherapeutic agents. The aim of the current study was to summarize the available clinical evidence on the role of the tamoxifen in different combination chemotherapy regimens because clinical studies including tamoxifen have produced inconclusive results. METHODS: The authors designed a systematic review and metaanalysis of published randomized controlled trials to assess the benefit of tamoxifen added to various single-agent or multiagent chemotherapy or biochemotherapy regimens. RESULTS: Six randomized trials met the inclusion criteria and were analyzed. These 6 trials involved a combined total of 912 patients. Of this number, 455 patients were randomized to receive tamoxifen added to chemotherapy or biochemotherapy regimens and 457 were randomized to receive chemotherapy or biochemotherapy without tamoxifen. The overall response rate was not improved significantly by the addition of tamoxifen to the chemotherapy regimen (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.75-1.82; test for overall effect: P = 0.14). The results were not statistically significant for complete response (OR, 0.64; 95% CI, 0.33-1.25; test for overall effect: P = 0.19). CONCLUSIONS: The current metaanalysis demonstrated that tamoxifen does not improve the overall response rate, complete response rate, or survival rate when administered along with combined chemotherapy regimens. Currently, the strength of evidence does not support the use of tamoxifen in combination with other systemic chemotherapy for the treatment of metastatic melanoma.

J Pediatr. 2003 Jul;143(1):60-6.
Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial.
Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH; McCune-Albright Study Group.
James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
OBJECTIVE: We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS). STUDY DESIGN: Girls < or =10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments. RESULTS: A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42+/-3.36/year vs 1.17+/-1.41/year), growth velocity slowed (SDS 1.22+/-2.65 vs -0.59+/-3.06, P=.005), and rate of bone maturation decreased (1.21+/-0.78 vs 0.72+/-0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred. CONCLUSIONS: Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.

Expert Opin Drug Saf. 2002 Sep;1(3):253-67.
Breast cancer chemoprevention: risk-benefit effects of the antioestrogen tamoxifen.
Brown K.
Cancer Biomarkers and Prevention Group, The Biocentre, University of Leicester, University Road, Leicester, LE1 7RH, UK.
The anti-oestrogen tamoxifen, which is widely used as adjuvant therapy for breast cancer, is undergoing evaluation as a chemopreventive agent in women at increased risk of developing this disease. Recent results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 prevention trial show a 49% reduction in breast cancer incidence in healthy, high-risk women. However, tamoxifen treatment has the serious side effect of increasing the incidence of endometrial cancer in women and long-term administration of tamoxifen causes hepatic tumours in rats. These liver tumours are induced via a genotoxic mechanism, but the mechanisms responsible for endometrial cancer in women are not yet known and are a focus of much debate. This review describes the findings from the chemoprevention trials and problems associated with the use of tamoxifen in this setting. The mechanism of carcinogenesis in rat liver is explained in detail and compared to the situation in humans, with a view to assessing the risks associated with tamoxifen therapy and predicting whether other anti-oestrogens might be safer alternatives.

Eur J Gynaecol Oncol. 2003;24(3-4):258-68.
Effects of tamoxifen on the human female genital tract: review of the literature.
Varras M, Polyzos D, Akrivis Ch.
Obstetrics and Gynaecology, G. Gennimatas, General State Hospital of Athens, Second District National Health System of Athens, Greece.
Tamoxifen is a non-steroidal triphenylethylene derivate, with clear antioestrogenic effects on the breast, that is orally administrated for the treatment of breast cancer and its prevention in a high-risk population. This article analyzes the effects of tamoxifen on the adult human female genital tract and considers its carcinogenicity in the gynaecological reproductive organs. It has been found that tamoxifen causes oestrogenic changes of the vaginal and cervical squammous epithelium and increases the incidence of cervical and endometrial polyps. The action of tamoxifen on the human endometrium in postmenopausal women is connected with simple oestrogenic effects including hyperplasia, while in others with endometrial cystic atrophy. In cases where tamoxifen induces endometrial polyps and hyperplasia, the extensive fibrosis accounts for difficulties in obtaining endometrial biopsy or resecting the polyps. In premenopausal patients tamoxifen disrupts the menstrual cycles and causes ovarian cysts, while in postmenopausal patients it induces ovarian cystic tumors and endometriomas. Also, postmenopausal patients treated with tamoxifen may develop endometriosis, adenomyosis and leiomyomata. In addition, randomized trials have shown a link between tamoxifen use in breast cancer patients and the development of endometrial carcinomas. Moreover, of note is the fact that the association of tamoxifen therapy with uterine mesenchymal neoplasms is higher than expected. In conclusion, the most worrying gynaecological side-effect of tamoxifen is the well-known increased risk of endometrial carcinomas. Women with breast cancer treated with tamoxifen should undergo annual gynaecological examination, but endometrial sampling should be obtained only in the event of endometrial bleeding.

J Clin Oncol. 2003 Jun 15;21(12):2276-81.
Randomized trial of 2 versus 5 years of adjuvant tamoxifen for women aged 50 years or older with early breast cancer: Italian Interdisciplinary Group Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01.
Sacco M, Valentini M, Belfiglio M, Pellegrini F, De Berardis G, Franciosi M, Nicolucci A; Italian Interdisciplinary Group for Cancer Care Evaluation.
Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy.
PURPOSE: To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer. PATIENTS AND METHODS: Women with breast carcinoma T1-3, N0-3, M0, who were between 50 and 70 years of age, were eligible irrespective of menopausal status, tumor grade, or estrogen receptor (ER) status. Patients who were event-free after 2 years of tamoxifen therapy were randomly assigned to stop or continue tamoxifen therapy for an additional 3 years. The primary end point was length of disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity. RESULTS: From 1989 through 1996, 1,901 patients were randomly assigned either to stop treatment (n = 958) or to receive tamoxifen for 3 additional years (n = 943). The median duration of postrandomization follow-up was 52 months. We found no statistically significant differences between the 5-year arm and the 2-year arm in terms of DFS (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76 to 1.08) and OS (HR, 1.16; 95% CI, 0.92 to 1.46). In ER-positive patients, a statistically significant prolongation of DFS related to longer treatment duration was observed (HR, 0.74; 95% CI, 0.59 to 0.93), whereas no difference in OS could be detected (HR, 0.98; 95% CI, 0.72 to 1.32). No differences in terms of endometrial cancers, cardiac or cerebrovascular events, or fractures were detected, whereas a doubling in the risk of thromboembolic events was found in the 5-year arm. CONCLUSION: Our results confirm previous research that shows that 5 years of tamoxifen decreases recurrence compared to 2 years in patients with ER-positive tumors.

Endocr Relat Cancer. 2003 Jun;10(2):267-77.
New approaches to the understanding of tamoxifen action and resistance.
Berstein LM, Zheng H, Yue W, Wang JP, Lykkesfeldt AE, Naftolin F, Harada H, Shanabrough M, Santen RJ.
Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia, PO Box 801416, Charlottesville, VA 22908, USA.
Tamoxifen (TAM) provides an effective agent for treatment of hormone-dependent breast cancer but resistance uniformly ensues upon continued use. Additional studies are required to define more precisely the mechanisms involved in development of resistance. We conducted systematic experimental and clinical studies based on the hypothesis that tumors exposed to TAM long-term may develop resistance by becoming hypersensitive to its estrogenic effects. These investigations uncovered new features of the TAM resistance (TR) phenomenon and identified possible means for its prevention and/or elimination. Initially we confirmed that TR may be divided into two subtypes, primary and acquired resistance, and that these differ by certain important characteristics including the level of the possible involvement of adaptive and genetic components. Then we distinguished at least three consequent stages of this phenomenon: stage I when TAM behaves as an antiestrogen, stage II with development of increased sensitivity to the agonistic (pro-estrogenic) properties of TAM and stage III with an adaptive increase in sensitivity to estradiol (E(2)). During this evolutionary process, as shown in vitro, MAP kinase (MAPK) and aromatase activities increase. The time frame of the increase in MAPK activity as a rule outpaces the increase in aromatase activity during the course of the development of TR. This may occur as a response to estrogen deprivation or interruption of the process of estrogen signaling and can be one of the promoting factors of increased aromatase activation. On the other hand, the chronology of these events indicates that changes in the MAPK cascade can be more important for the early steps of the development and maintenance of the TR state. Changes in local estrogen production/sensitivity to E(2) are perhaps essential for the later steps of this phenomenon. We have explored the use of a growth factor-blocking agent to abrogate the adaptive changes in sensitivity. Farnesylthiosalicylic acid (FTS), an inhibitor of GTP-Ras binding to its membrane acceptor site, reduces the increase in the number of MCF-7 cells induced by long-term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TR cell lines. Alone or in combination with letrozole (presumably, through the influence on MAPK pathway) FTS exerts moderate inhibitory effects on aromatase activity in estrogen-deprived or estrogen-exposed MCF-7 cells. Taken together, our observations suggest that FTS is a 'candidate drug' for the treatment of TR. Both the adaptive and genetic types of resistance may be amenable to this approach. Our studies underline the possible importance of starting the treatment/prevention of TR early on. From our clinical studies using immunohistochemistry, there is a rather strong rationale to include as a predisposing factor in the development of TR the increase in MAPK and aromatase activities in human primary breast tumors. In summary, data obtained during the course of this project may be considered as evidence supporting the principle that processes resulting in responses to TAM as an agonist and the development of estrogen hypersensitivity of breast cancer cells could potentially be mechanistically linked.

Eur J Cancer. 2003 May;39(7):891-8.
Effects of low dose tamoxifen on normal breast tissue from premenopausal women.
de Lima GR, Facina G, Shida JY, Chein MB, Tanaka P, Dardes RC, Jordan VC, Gebrim LH.
Department of Gynecology, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil.
The aim of this study was to determine the effects of low doses of tamoxifen (5 and 10mg/day) for 50 days compared with the standard dose (20 mg/day) on breast biomarkers measured in normal breast tissue from premenopausal patients. A randomised double-blind study was performed using tissue from 56 premenopausal women with a diagnosis of fibroadenoma of the breast. Excisional biopsy was performed on the 50th day of therapy. Normal breast tissue samples were collected during surgery. The patients were divided in groups: A (placebo, n=11); group B (5 mg, n=16), group C (10 mg, n=14) and group D (20 mg, n=15). In this cross-sectional study, differences in the expression of Oestrogen Receptor alpha (ERalpha), Progesterone Receptor (PR), Ki-67, apoptotic bodies and mitotic index between the different groups after treatment can be seen on the normal breast tissue. We believe that a lower dose of tamoxifen could reduce the side-effects associated with treatment without affecting its chemopreventive activity in the breast.