Fareston scientific update |
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Ann N Y Acad Sci. 2006 Dec;1092:374-84.
Christodoulakos GE, Lambrinoudaki IV, Botsis DC.
econd Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, Athens, Greece.
The cardiovascular effects of selective estrogen receptor modulators.
Coronary artery disease (CAD) is the main contributor of mortality among postmenopausal women. Menopause-associated estrogen deficiency has both metabolic
and vascular consequences that increase the risk for CAD. Hormone therapy (HT) has been reported to have a beneficial effect on metabolic and vascular
factors influencing the incidence of CAD. Although observational studies have reported that HT reduces significantly the risk for CAD, randomized clinical
trials (WHI, HERS, ERA) have questioned the efficacy of HT in primary and secondary CAD prevention despite confirming the lipid-lowering effect of HT. In the
aftermath of the WHI, increased interest has been given to the action of selective estrogen receptor modulators (SERMs) and their effect on the
cardiovascular system. The chemical structure of SERMs, either triphenylethilyn (tamoxifen) or benzothiophene (raloxifene) derivatives, differs from that of
estrogens. SERMs are nonsteroidal molecules that bind, with high affinity, to the ER. SERMs induce conformational changes to the ligand-binding domain of the
ER that modulate the ability of the ER to interact with coregulator proteins. The relative balance of coregulators within a cell determines the
transcriptional activity of the receptor-ligand complex. SERMs therefore may express an estrogen-agonist or estrogen-antagonist effect depending on the
tissue targeted. SERMs express variable effects on the metabolic and vascular factors influencing the incidence of CAD. SERMs have been reported to modulate
favorably the lipid-lipoprotein profile. Toremifene expresses the most beneficial effect followed by tamoxifene and raloxifene, while ospexifene and HMR-3339
have the least effect and may even increase triglycerides. Raloxifene and tamoxifene decrease serum homocysteine levels and C-reactive proteins (CRP), which
are both markers of CAD risk. Raloxifene has been reported to increase the nitric oxide (NO)-endothelin (ET)-1 ratio and, thus, contribute to proper
endothelial function and vasodilation. Toremifene has no effect on the NO-ET-1 ratio. Finally, raloxifene decreases the vascular cell adhesion molecules and
the inflammatory cytokines TNF-alpha and IL-6. Of the SERMs, raloxifene has had the most extensive evaluation regarding the effect on the vascular wall of
endothelium. Although not confirmed by large clinical trials, raloxifene has been reported to have an effect on the cohesion of the intercellular junction
(VE-cadherin) and the synthesis-degradation of extracellular matrix (MMP-2). The Multiple Outcomes Raloxifene Evaluation (MORE) study has reported that
raloxifene may have a cardioprotective effect when administered to postmenopausal women at high risk for CAD disease.
Fertil Steril. 2007 Apr 3;
Farmakiotis D, Farmakis C, Rousso D, Kourtis A, Katsikis I, Panidis D.
Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
The beneficial effects of toremifene administration on the hypothalamic-pituitary-testicular axis and sperm parameters in men with idiopathic oligozoospermia.
OBJECTIVE: To evaluate whether toremifene, a selective estrogen receptor modulator (SERM), has a beneficiary effect on all three main sperm parameters.
DESIGN: Prospective interventional clinical study. SETTING: University hospital. PATIENT(S): One-hundred subfertile men with idiopathic oligozospermia.
INTERVENTION(S): Toremifene (60 mg daily) was administered to all men for 3 months. At baseline and at the end of each month, serum concentrations of
follicle-stimulating hormone (FSH), testosterone, inhibin B, and sex hormone-binding globulin (SHBG) were measured. At baseline and at the end, semen
analysis was performed and sperm concentration, spermatozoal motility and normal sperm forms were determined. MAIN OUTCOME MEASURE(S): Gonadotropin,
testosterone, inhibin-B levels, total sperm count, sperm morphology and motility. RESULT(S): Toremifene administration resulted in a significant increase in
FSH, testosterone, SHBG, and inhibin B levels, as well as in sperm concentration, percentage motility and normal sperm forms. Twenty-two men's partners
achieved pregnancy within 2 months of the end of treatment. At the end of the third month, serum FSH levels were significantly higher in the men whose
partners did not achieve pregnancy, and total sperm count and normal sperm forms were significantly lower compared with the group of men whose partners
achieved pregnancy. CONCLUSION(S): Toremifene administration for a period of 3 months in men with idiopathic oligozoospermia is associated with significant
improvements of sperm count, motility, and morphology, mediated by increased gonadotropin secretion and possibly a direct beneficial effect of toremifene on
the testes. The above findings are also indicative of a better testicular exocrine (improved sperm parameters) response to treatment in men whose partners
achieved pregnancy compared with those who did not. Further randomized, placebo-controlled trials should be conducted to determine whether this particular
selective estrogen receptor modulator can be useful as an initial approach in men with oligozoospermia.
Menopause Int. 2007 Mar;13(1):27-34.
Palacios S.
Palacios Institute of Women's Health, Madrid, Spain.
The future of the new selective estrogen receptor modulators.
Selective estrogen receptor modulators (SERMs) are compounds that display mixed estrogen agonist/antagonist activity. Currently, four SERMs are licensed for
clinical use: tamoxifen, toremifene, clomifene and raloxifene. The STAR and RUTH trials have provided useful data about the potential role of SERMs in the
primary prevention of breast cancer and cardiovascular disease in postmenopausal women. New-generation SERMs, such as bazedoxifene, arzoxifene, lasofoxifene
and ospemifene, are currently being evaluated. The aim is to find a SERM that conserves the skeleton and prevents breast cancer without increasing the risk
of endometrial cancer and venous thromboembolism, and without inducing hot flushes. Technological advances in the study of estrogen receptor activation will
provide key information for drug development.
Rev Urol. 2005;7 Suppl 3:S30-5.
Smith MR.
Selective estrogen receptor modulators to prevent treatment-related osteoporosis.
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, which is a leading cause of osteoporosis in men. Consistent with this observation, GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. GnRH agonists markedly decrease serum levels of both testosterone and estrogen. Estrogens play a central role in homeostasis of the normal male skeleton, and the available evidence suggests that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects of GnRH agonists. The central role of estrogens in male bone metabolism provides a strong rationale to evaluate selective estrogen receptor modulators for prevention of treatment-related osteoporosis in men with prostate cancer. Preliminary evidence suggests that both raloxifene and toremifene increase bone mineral density in GnRH agonist-treated men. An ongoing pivotal study will evaluate the effects of toremifene on fractures and other complications of GnRH agonists in men with prostate cancer.
Anticancer Drugs. 2003 Apr;14(4):265-73.
Vogel CL.
Cancer Research Network, Plantation, FL, USA.
Update on the current use of hormonals as therapy in advanced breast cancer.
Hormonal agents have a confirmed role in the management of postmenopausal women with receptor-positive advanced breast cancer. Until recently, tamoxifen has been the accepted agent for treating these patients. However, accumulating evidence suggests that the new antiaromatase agents will replace the antiestrogens as the preferable option in hormone-naive patients. Comparative trials indicate that the aromatase inhibitors, anastrozole and letrozole, and the aromatase inactivator, exemestane, have at least equivalent efficacy to tamoxifen with similar or superior tolerability. These agents are also more effective than the progestin, megestrol acetate, when studied in patients progressing on tamoxifen. The improved aromatase selectivity and high potency of these antiaromatase agents when compared with earlier agents have resulted in improved efficacy and tolerability. Additionally, no cross-resistance has been reported between the antiaromatase agents and tamoxifen or, in some instances, among the antiaromatase agents themselves. The role of antiaromatase agents will certainly expand in the near future to include not only treatment of metastatic breast cancer, but use in the adjuvant and neoadjuvant settings as well, and, ultimately, breast cancer prevention. The results of ongoing investigations are awaited with interest.
Pharmacol Toxicol. 2003 Oct;93(4):174-9.
Maenpaa H, Saransaari P, Tahti H.
Medical School, University of Tampere, Tampere, Finland.
Kinetics of inhibition of glutamate uptake by antioestrogens.
The antioestrogens, tamoxifen and its more recent homologue toremifene, are used in the therapy of breast cancer. Tamoxifen has been reported to cause retinal changes as side effects. Both compounds inhibited glutamate uptake in retinal pigment epithelial cells, and the present study was conducted to clarify the mechanism of this inhibition. Retinal pigment epithelial cells are part of the blood-retina barrier, and their glutamate transporters are essential for retinal glutamate homeostasis. Glutamate uptake was investigated in human retinal pigment epithelial cell line D407 and in cultured pig retinal pigment epithelial cells using L-[3H]glutamate as a tracer. The cells were exposed to 7.5 microM tamoxifen and toremifene. beta-Hydroxyaspartate, a transportable inhibitor of glutamate transport, was used as a reference compound. In kinetic analyses, beta-hydroxyaspartate increased the Km constant for glutamate transport. Tamoxifen and toremifene exhibited the same effect, which indicates that inhibition evoked by them is also competitive in nature. Both drugs were more effective in the human retinal pigment epithelial cell line than in the pig retinal pigment epithelial cells. The results show for the first time that the antioestrogens tamoxifen and toremifene could possibly hamper glutamate transport by replacing glutamate as the substrate.
Magy Onkol. 2003;47(2):133-40. Epub 2003 Sep 16.
Eckhardt S.
Orszagos Onkologiai Intezet, Budapest 1122, Hungary.
Perspectives for the hormonal therapy of breast cancer.
The role of estrogens, including its sources, tissue distribution, metabolism, and mechanism of action, is discussed in this review. The ER alpha and beta are functioning separately, and there is a physiological balance between their activity. Whenever this balance is over thrown due to endogenous or exogenous carcinogenic factors, malignancy develops. Risk factors of breast cancer are listed and evaluated individually. It should be stressed however, that their carcinogenic effect sums up. The knowledge of established risk factors rises the possibility of chemoprevention, which might be highly desirable in case of gene carriers. Special emphasis is attached to the SERM molecules which act as antiestrogens. Their antitumour effect is largely used in the treatment of hormone sensitive advanced breast cancer patients, and their efficacy has been proved in adjuvant therapy as well. Their preventive use might also be justified, especially in gene carriers. Aromatase inhibitors form a special class among the SERM molecules. In Hungary, anastrozole, letrozole and exemestane are widely applied for the therapy of breast cancer patients, while raloxifene has only been introduced recently, mainly in order to prevent osteoporosis. The therapeutic value of fulvestrant is unknown yet and its antitumour effect has to be explored. The therapeutic significance of these molecules lies in the fact that they might be effective after the development of tamoxifen resistance. There are several explanations for this phenomenon offering new targets for the further development of a succesful antitumour chemotherapy.
Gan To Kagaku Ryoho. 2003 May;30(5):669-75.
Maruyama S, Kuroiwa S, Saimoto A, Nishikawa K.
Research and Development Division, Nippon Kayaku Co., Ltd.
Combined effects of toremifene and paclitaxel on human breast cancer cell lines.
Effects of toremifene (TOR) in combination with paclitaxel (TXL) on various human breast cancer cell lines were evaluated. TOR and TXL exhibited additive effects on estrogen receptor (ER)-positive cancer cell lines, MCF-7 and T-47D, and a sub-additive effect on a tamoxifen (TAM)-resistant line, T-47D/TAM. To all three ER-negative cancer cell lines, the combined treatment also showed additive effects on MDA-MB-134VI, MDA-MB-231 and MDA-MB-453. Furthermore, a synergistic effect was observed on a multi-drug resistant (MDR) line, Adr. This synergistic effect was more potent in the combination with TOR than that with TAM. The combined treatment increased intracellular TXL, and the accumulation by TOR was 1.5-fold that by TAM. Consequently, the ratio of G2M arrested cells was higher, with statistical significance, in the TOR combination than in the TAM combination. In addition, these synergistic effects in MDR cells were also observed in the combination of TXL with major clinical active metabolites, N-desmethyl-TOR (TOR-1) and 4-hydroxy-TOR (TOR-2). These results suggest that the combination therapy of TOR and TXL might be an effective clinical treatment for breast cancer patients.
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Drug category:Anti-cancer drugs
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