Tamoxifen scientific update |
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J Pediatr. 2004 Jul;145(1):71-6.
Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.
Department of Pediatrics, University of Ottawa, Ontario, Canada.
Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.
A report on the treatment of pubertal gynecomastia using raloxifene and tamoxifen and it effectiveness. The study aims to assess the efficacy of the anti-estrogens such as tamoxifen and raloxifen in the treatment of pubertal gynecomastia. It is found that estrogen receptor inhibition in the breast is safe in reducing persistent pubertal gynecomastia.
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.
Cochrane Database Syst Rev. 2004;(3):CD001024.
Nowak A, Findlay M, Culjak G, Stockler M.
Tamoxifen for hepatocellular carcinoma.
Efficacy of Tamoxifen in the treatment of hepatocellular carcinoma. It is the main cause which increases cancer mortality world-wide. Trials of tamoxifen for hepatocellular carcinoma are not positive.
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.
Anticancer Drugs. 2004 Aug;15(7):707-714.
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.
Reduction of tamoxifen resistance in human breast carcinomas by tamoxifen-containing liposomes in vivo.
A study was conducted recently to check whether it is possible to reduce anti-estrogen resistance in breast using liposomally encapsulated tamoxifen in vivo. Liposomally encapsulated tamoxifen has uterotrophic properties similar to the dissolved compound. This study proved that tamoxifen is best to make pharmacological effects and to pick up the therapeutic effectiveness in quite a few anti-estrogen-resistant xenografts.
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.
Chem Biol Interact. 2004 Jul 20;148(3):149-61.
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.
Protection of tamoxifen against oxidation of mitochondrial thiols and NAD(P)H underlying the permeability transition induced by prooxidants.
A new research was carried out to test the effectiveness of tamoxifen on the mitochondrial permeability transition. The test is underlaid by the permeability transition induced by prooxidants. The researches suggests a possible ER-independent mechanism for the efficiency of this drug in the cancer therapy and prevention.
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.
Eur J Cancer. 2005 Mar;41(4):647-54. Epub 2005 Jan 18.
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 soy isoflavone daidzein improves the capacity of tamoxifen to prevent mammary tumours.
Mammary tumours can be prevented by the co administration of soy isoflavone daidzein with tamoxifen. Soy isoflavone daidzein is capable to increase the capacity of tamoxifen. The combination of daidzein with tamoxifen can give increased protection against mammary carcinogenesis.
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.
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Drug category:Anti-cancer drugs
 Tamoxifen scientific update
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