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PubMed2005

Dose-dependent effects of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on estrogen receptor-alpha expression in the rat uterus.

Tamoxifen, a selective estrogen receptor modulator, has agonist or antagonist activity, depending on the target tissue. The estrogen-like agonist effects of tamoxifen in the uterus are mediated primarily by 4-hydroxytamoxifen (4OH), the major active metabolite. Tamoxifen, 4OH and estradiol-17beta (E2) all bind to estrogen receptors (ERalpha and ERbeta), but with different affinities, suggesting that these ligands are capable of producing differential in vivo effects on the uterus. However, differences in short-term effects of tamoxifen, 4OH and E2 on the uterus have not been compared in the rat in vivo. Thus, we treated adult, ovariectomized rats (225-250 g) with vehicle (sesame oil), tamoxifen (1 mg/kg body weight), 4OH (0.01, 0.1 or 1.0 mg/kg body weight), E2 (40 microg/kg body weight), estradiol valerate (a long-lasting estrogen; 40 microg/kg body weight) or ICI 182,780 (a pure anti-estrogen; 1 mg/kg body weight). Animals were sacrificed at 0, 3, 6, 12 or 24 h post-injection, and protein and mRNA levels for ERalpha and two estrogen-regulated early response genes, c-fos and jun-B, were examined. Administration of E2 and 4OH (1 mg/kg body weight dose) resulted in down-regulation of uterine ERalpha protein in the uterine luminal and glandular epithelium by 6 h post-treatment. In contrast, no change in ERalpha level was observed after treatment with tamoxifen. Rapid (by 3 h) and transient increases in c-fos and jun-B mRNA levels were observed after E2 treatment; however, c-fos and jun-B induction by 4OH was highly dose dependent, and higher 4OH doses induced rapid but persistent proto-oncogene expression in vivo. Our results demonstrate that tamoxifen and its major metabolite have differential effects on uterine gene expression, and 4OH is highly estrogenic in the rat uterus.

Animals↗
PubMed2005

Estrogen receptor (ER) gene polymorphism may predict the bone mineral density response to raloxifene in postmenopausal women on chronic hemodialysis.

The estrogen receptor (ER) gene has been considered as a candidate genetic marker for osteoporosis, and PvuII and XbaI polymorphisms of the ERalpha gene have been associated with low bone mineral density (BMD). We investigated whether ER polymorphism could predict the response of BMD in 28 postmenopausal women on hemodialysis with marked osteopenia or osteoporosis, randomized to receive raloxifene, a selective estrogen receptor modulator (SERM), or placebo for 1 year. BMD was assessed by dual X-ray absorptiometry and PvuII and XbaI restriction fragment-length polymorphism of the ER gene was determined using polymerase chain reaction. Baseline lumbar spine or femoral neck BMD parameters were not different between patients presenting either homozygous PP or xx when compared with heterozygous Pp or Xx genotypes. After 1 year, patients on raloxifene, presenting with PP or xx genotypes (but not those with Pp or Xx), showed a significantly higher mean lumbar spine BMD (0.942 +/- 0.18 vs. 0.925 +/- 0.17 g/cm2, p < .01) and lower serum pyridinoline (19.7 +/- 9.7 vs. 30.6 +/- 16.5 nmol/L, p < .02) when compared with baseline values. No changes were detected in the placebo-treated patients or in the femur neck sites. In conclusion, after 1 year on raloxifene, postmenopausal osteoporotic women on chronic hemodialysis, homozygous for the P or x (PP or xx) alleles of the ER, exhibited a better lumbar spine BMD response and decreased serum pyridinoline values when compared with heterozygous women (Pp or Xx), suggesting that ERalpha allelic variants may explain, at least in part, the different outcomes after treatment of osteoporosis with SERM.

Aged↗
PubMed2003

De novo design, synthesis and evaluation of a non-steroidal diphenylnaphthyl propylene ligand for the estrogen receptor.

There is still a strong need for additional diversity and new chemical scaffolds to allow for the exploration of improved tissue selectivity and finding better selective estrogen receptor modulators (SERMs). Using a de novo design technology a diphenylnaphthyl propylene scaffold, exemplified by (E)-9b, with ER antagonist activity has been generated. It was prepared by alkylating 1-[4-methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl]-1-propanone under metal halogen exchange conditions with 1-iodo-6-methoxy-naphthalene. Following dehydration and cleavage of the methoxy groups, (E)-9b was formed by displacement of the chloro group with pyrrolidine. (E)-9b binding to ER generated calculated K(i) values of 3.7 nM for hER(alpha) and 72 nM for hER(beta). The antagonism of (E)-9b was demonstrated in cell transfection assays using the ERE from the vitA2 promotor and the natural ER-responsive pS2 promotor. With increasing concentrations of (E)-9b, the E(2)-dependent response was efficiently inhibited demonstrating that (E)-9b could function as an anti-estrogen in these assays. Interestingly, ER(alpha) activity was inhibited even below basal levels suggesting that ligand-independent activity of ER(alpha) was also inhibited. Computational docking studies suggest that the placement of the hydroxyl group on the naphthalene group may not be optimal and we are currently exploring additional analogues.

Cells, Cultured↗
PubMed2002

Chemoprevention of breast cancer: implications for postmenopausal women.

Estrogen administration is associated with reduction in perimenopausal symptoms and the risk for several conditions affecting postmenopausal women. As estrogen administration also increases the risk for breast cancer, a common dilemma facing many women and their physicians is whether to use estrogen replacement therapy (ERT), a selective estrogen receptor modulator (SERM) that antagonises estrogenic effects in breast tissue but retains some estrogen agonist properties in other organs, or neither. For women with average to moderate risk of breast cancer and with perimenopausal symptoms, ERT may be the best short-term choice. For very high-risk women (>1% per year) with menopausal symptoms, alternatives to ERT might be offered and tried first. A diagnosis of ductal carcinoma in situ or invasive breast cancer within the last 2 to 5 years should be considered a relative contraindication for ERT unless the tumour was estrogen receptor negative. High-risk women without menopausal symptoms are the best candidates for the only currently approved drug for breast cancer risk reduction, tamoxifen. Although the drug is approved for women with a 5-year risk of breast cancer > or = 1.7% (0.34% per year), postmenopausal women most likely to experience a favourable benefit/risk ratio are those with a Gail estimated risk of >0.5% per year without a uterus or >1% per year if they retain their uterus. Tamoxifen should not be used in women with prior history of thromboembolic or precancerous uterine conditions. Tamoxifen is often used in Europe in conjunction with transdermal ERT in hysterectomised women without obvious loss of efficacy or increased risk of thromboembolism. Raloxifene is a second generation SERM with estrogen-like agonist effects on bone but with less uterine estrogen agonist activity than tamoxifen. Raloxifene may have less potent breast antiestrogenic effects than tamoxifen, particularly in a moderate- to high-estrogen environment. Raloxifene is approved for use in reducing risk of osteoporosis, but not breast cancer. Whether it is as effective as tamoxifen in reducing breast cancer risk in postmenopausal women is the subject of a current trial. All women regardless of breast cancer risk are advised to employ nonpharmacological risk reduction measures, including normalisation of bodyweight, exercise, adequate calcium and vitamin D intake, and avoidance of smoking and alcohol. The preventive options are best weighed during an individualised consultation where a woman's menopausal symptoms and risk for breast cancer and other diseases can be examined, and the options for improving postmenopausal health can be discussed.

Anticarcinogenic Agents↗
PubMed2002

Differential SERM effects on corepressor binding dictate ERalpha activity in vivo.

Selective estrogen receptor modulators (SERMs) show differential effects upon ERalpha activation function 1 (AF-1). Tamoxifen allows strong ERalpha AF-1 activity, whereas raloxifene allows less and ICI 182,780 (ICI) allows none. Here, we show that blockade of corepressor histone de-acetylase (HDAC) activity reverses the differential inhibitory effect of SERMs upon AF-1 activity in MCF-7 cells. This suggests that differential SERM repression of AF-1 involves HDAC-dependent corepressors. Consistent with this, ICI and raloxifene are more potent than tamoxifen in promoting ERalpha-dependent sequestration of progesterone receptor-associated corepressors. Moreover, ICI and raloxifene are more efficient than tamoxifen in promoting ERalpha binding to the corepressor N-CoR in vivo and in vitro. An ERalpha mutation (537X) that increases N-CoR binding in the presence of all SERMs blocks AF-1 activity. An ERalpha mutation (L379R) that decreases N-CoR binding increases AF-1 activity in the presence of ICI and raloxifene and reverses the effect of the 537X mutation. The 537X and L379R mutations also alter the ligand preference of ERalpha action at AP-1 sites and C3 complement, an action that also involves AF-1. Together, our results suggest that differential SERM effects on corepressor binding can explain differences in SERM effects on ERalpha activity. We propose a model for differential effects of SERMs on N-CoR binding.

Antineoplastic Agents, Hormonal↗
PubMed2005

Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways.

17beta-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 mum) increased both the expression and release of the neuroprotective cytokines, TGF-beta1 and TGF-beta2 (TGF-beta), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-beta. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-beta, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-beta immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-beta release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-beta expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

Animals↗
PubMed2005

Investigations on the effects of basic side chains on the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines.

Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-ylethane, or a pyrrolidin-1-ylethane side chain into one of the 4-hydroxyphenyl rings. The compounds were tested for agonistic and antagonistic activity on hormone sensitive, ERalpha-positive MCF7-2a cells, stably transfected with the plasmid ERE(wtc)luc and on U-2 OS cells transiently transfected with plasmids encoding for ERalpha (pSG5-ERalpha) or ERbeta (pSG5-ERbeta FL) as well as the reporter plasmid (ERE)(2)luc(+). Despite the presence of a basic side chain, the majority of the 4,5-diaryl-2-imidazolines showed agonistic effects. The most active compound, (4R,5S)/(4S,5R)-4-(2-chloro-4-(2-piperidin-1-ylethoxy)phenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline (5a), achieved at ERalpha an EC(50) value of 0.085 microM and at ERbeta an EC(50) = 0.40 microM. High antagonistic properties only possessed the C2 ethyl substituted compounds 2a and 4a. (4R,5S)/(4S,5R)-2-Ethyl-4-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-ylethoxy)phenyl)-2-imidazoline (2a) reduced the effect of estradiol at ERalpha strongly with IC(50) = 0.038 microM, while its antagonistic properties at ERbeta were distinctly lower (IC(50) = 9.00 microM), probably due to the partial agonistic effects (EC(50) = 0.50 microM).

Cell Line, Tumor↗
PubMed2000

Raloxifene: a review of its use in postmenopausal osteoporosis.

UNLABELLED: Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.

Bone Remodeling↗
PubMed2003

Adverse effects of a SERM (Levormeloxifene). Safety parameters and bone mineral density 12 months after treatment withdrawal.

OBJECTIVE: Levormeloxifene is a selective estrogen receptor modulator (SERM). The development of the drug was discontinued due to intolerable adverse effects. This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with levormeloxifene. METHODS: Adverse events were recorded at all clinical visits. The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography. Endometrial biopsies were obtained by pipelle. The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance. Bone mineral density of the total body, lumbar spine (L1-L4), hip and forearm was measured by dual-energy X-ray absorptiometry. RESULTS: The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm. No cases of proliferative endometrium were reported. Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner. Hysteroscopic examinations showed that levormeloxifene was related to increased incidence of edema, vascularization and cysticity. In the levormeloxifene groups, a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence (including worsening of a previously existing condition). Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment. CONCLUSION: Endometrial thickening, seen in association with the use of some SERM's, may lead to harmful adverse effects more than 12 months after treatment is initiated. Levormeloxifene prevents the postmenopausal bone loss, but the lowest effective dose is unknown.

Bone Density↗
PubMed2001

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.

Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.

Aged↗
PubMed2003

Tamoxifen induces gonadotropin-releasing hormone self-priming through an estrogen-dependent progesterone receptor expression in the gonadotrope of the rat.

Tamoxifen (TX) is an antiestrogen with varying levels of antagonist/agonist activity on the reproductive axis of the rat. It has been reported that TX, in contrast to other selective estrogen receptor modulators (SERMs), increases the content of cytosolic estrogen receptors (ER) in the gonadotrope and induces gonadotropin releasing hormone (GnRH) self-priming in the absence of E. GnRH priming is believed to be a consequence of E-dependent progesterone receptor (PR) activation. The purpose of this study was to determine whether TX induces PR expression in the gonadotrope in an E-dependent manner, and whether the blockade of PR activation affects TX-dependent GnRH self-priming in ovariectomized (OVX) rats. Chronic OVX rats were injected (sc) over 3 days with 25 microg estradiol benzoate (EB), 3 mg TX, 0.5 mg RU58668, a 'pure' anti-E (aE), 2 mg RU38486, an anti-P at the receptor (aP), TX+aE and TX+aP. Controls were given 0.2 ml oil. While EB and TX increased mRNA for both PR A+B and PR B expression and the number and intensity of nuclei immunoreactive (IR) for PR in the gonadotrope, the aE and aP given alone had no effect on either PR mRNA levels or nuclear PR-IR. The aE reduced the effect of TX on PR expression (mRNA and nuclear IR) while the aP slightly reduced nuclear PR-IR only. In addition, pituitaries from each of the seven groups were incubated with: 10(-8)M E(2), 10(-7)M TX, 10(-8)M aE, 10(-8)M aP, TX+aE, TX+aP or medium alone, respectively. Pituitaries were tested for GnRH self-priming (two pulses of 15 min 1 h apart) and the secretion of LH and PRL determined by specific RIAs. Pituitaries from rats treated with EB and incubated with E(2) had increased basal and GnRH-stimulated luteinizing hormone (LH) and prolactin (PRL) secretion and GnRH self-priming. TX reduced basal and stimulated LH secretion, increased PRL secretion and induced a robust GnRH self-priming. All these effects of TX were blocked by the aE, while the aP blocked GnRH self-priming only. In conclusion, tamoxifen induced PR expression (mRNA and nuclear IR) in the gonadotrope in an E-dependent manner, while activation of these PR through intracellular signaling of GnRH induced GnRH self-priming.

Animals↗
PubMed2005

Lasofoxifene: CP 336156, CP-336156.

Lasofoxifene [CP 336156] is a potent, nonsteroidal, tissue-selective estrogen receptor modulator (SERM). It has the bone-sparing and cardioprotective effects of estrogen, but lacks estrogen's uterine cancer risk. Lasofoxifene is under development with Ligand Pharmaceuticals and Pfizer (formerly Parke-Davis) for the prevention of postmenopausal osteoporosis and breast cancer. In June 2000, Parke-Davis' parent company, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development. The discovery of lasofoxifene resulted from a research collaboration between Pfizer and Ligand Pharmaceuticals. There was a contract dispute between the two companies relating to their research agreement. Under a settlement of litigation, Ligand is entitled to milestone and royalty payments. If Pfizer is successful in developing the drug through to regulatory approval in the US, Ligand could receive royalty revenues from lasofoxifene as early as 2003-2004. The royalties will be equal to 6% of net sales and will be in addition to milestone payments for continuing development of the drug. However, on 6 March 2002, Ligand Pharmaceutical announced an agreement with Royalty Pharma in which the latter purchased the rights to a share of these future payments. Under the agreement, Ligand received US dollars 6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Royalty Pharma retains the option to purchase, at escalating prices, additional rights (subject to timing restrictions) to extend this stake up to 1.0%, for a total of US dollars 56 million. In April 2002, Royalty Pharma exercised its first option to purchase an additional 0.125% of potential future sales of the three SERMS in exchange for US dollars 3 million. Subsequently, in December 2002, Royalty Pharma exercised an expanded option and agreed to pay Ligand US dollars 6.775 million for 0.1875% of potential future sales of SERM products. Royalty Pharma and Ligand Pharmaceutical amended their royalty agreement in October 2003 for the three SERM products. Under the amended agreement, Royalty Pharma exercised an option to pay Ligand US dollars 12.5 million, plus cumulative milestones of up to US dollars 2.5 million upon the launches of the three SERMs (provided they are approved by 30 September 2005), in exchange for 0.7% of potential future sales of the products for 10 years. In November 2004, Ligand Pharmaceuticals and Royalty Pharma further amended their existing royalty agreement for the three SERM products. Under the terms of the revised agreement, Royalty Pharma will purchase an additional 1.625% of the SERM products' net sales for US dollars 32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following the first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets will be paid to Ligand as earned and are not included in this amended agreement. In September 2004, Ligand Pharmaceuticals earned a milestone payment of approximately US dollars 2 million from Pfizer, payable in 181,818 shares of Ligand stock held by Pfizer. The payment was triggered by Pfizer's NDA submission for lasofoxifene in August 2004. Under the terms of the agreement between Ligand and Pfizer, Ligand is entitled to receive an additional milestone upon successful approval of lasofoxifene. On 19 August 2004, Pfizer filed an NDA with the US FDA for lasofoxifene for the prevention of osteoporosis in postmenopausal women. Product launch is forecasted to occur in 2006-2007. Ligand reported in January 2004 at the 22nd Annual JP Morgan Healthcare Conference that it anticipated the availability of phase III data and NDA filing sometime in 2004. Lasofoxifene has undergone two phase III studies with Pfizer in the US as an orally administered therapy for postmenopausal osteoporosis. In June 2003, Pfizer reported that enrolment was completed in a trial evaluating lasofoxifene in the prevention of bone loss. The trial also evaluated lasofoxifene's effect on lipid levels. The trial enrolled approximately 2000 postmenopausal women. Another trial was conducted among 8500 patients to investigate lasofoxifene in the treatment of fractures. In addition, Pfizer began a third worldwide phase III trial to evaluate whether lasofoxifene reduced the risk of vertebral fractures, breast cancer and cardiovascular disease. At the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003), Ligand also confirmed that lasofoxifene was in phase III development for breast cancer. Lasofoxifene is under clinical evaluation as a treatment for vaginal atrophy. According to Pfizer's pipeline in November 2004, the company anticipates regulatory submission for vaginal atrophy by the end of 2004. In June 2002, Ligand estimated that lasofoxifene has the potential to reach sales of US dollars 1-2 billion, pending approval.

Adult↗
PubMed2003

Therapeutic androgen receptor ligands.

In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs).

Journal Article↗
PubMed2002

[Estrogen replacement therapy: for whom, why and how?].

Symptoms may appear during the perimenopause, but it is often difficult to treat them at that time. Progestins are used to treat abnormal bleeding. Low dose hormone replacement therapy (HRT) or oral contraception are often used also. HRT can be used to maintain the bone density even in elderly women. Nevertheless, the treatment is often not taken for sufficient time. In order to improve compliance, a number of low dose HRT have been developed. For most patients these medications will preserve the bone mass, but data showing a fracture protection are missing. The exact role of HRT on cardiovascular pathologies is controversial. Observational data indicated a protective effect on atherosclerosis. But randomised studies contradicted these results: the latest randomised trial involving a continuous combined regimen of estrogen and progestin reported an increased risk in cardiovascular events as compared to placebo. It is still possible that estrogen decreases atheromatosis but that it increases the risk of thrombosis. SERM (Selective Estrogen Receptor Modulators) have agonistic and antagonistic proprieties to estrogens on selective tissues. They have a proven protective effect on bone and possibly also on cardiovascular system. Nevertheless, the risk of thrombosis seems to be similar to that of estrogens. The risk of breast cancer seems to be increased in long term HRT users but this subject is also controversial since discordant results have been reported. Furthermore, breast cancer mortality in HRT users seems to be lower than in non users.

Breast Neoplasms↗
PubMed2005

The estrogen receptor modulator tamoxifen enhances spontaneous glycinergic synaptic inhibition of hypoglossal motoneurons.

Tamoxifen (Tam), a widely used anticancer agent, is now also used for healthy women with risk of breast cancer. Furthermore, it is the prototype of the selective estrogen receptor modulator family, with promise for neuroprotection. However, possible effects on neurotransmission have been little explored. Recently, Tam was shown to potentiate chloride responses to low concentrations of exogenous glycine in cultured spinal neurons from rat embryo. The present study investigates the possible modulation by Tam of the spontaneous synaptic glycinergic activity recorded from voltage-clamped hypoglossal motoneurons, using the whole-cell patch-clamp technique in brainstem slices from juvenile rat. Miniature currents were isolated with tetrodotoxin. Tam increased the mean amplitude of glycinergic miniature currents, by 68-79% at 2 microM (in nine of 10 cells) and by 47% at 0.5 microM (in four of nine cells). Furthermore, Tam markedly increased the frequency of glycinergic miniatures, by a factor reaching 15 in some neurons, even in the presence of the Ca2+ channel blocker Cd2+. Tam also increased the frequency of the total spontaneous glycinergic activity without tetrodotoxin. The increase in miniature amplitude is consistent with the increase in postsynaptic glycine receptor sensitivity previously reported. The increase in frequency indicates an additional presynaptic effect. Addition of exogenous glycine could also increase the frequency of glycinergic miniatures. Thus, one of the presynaptic effects of Tam might be potentiation of the basal activity of presynaptic glycine receptors facilitating glycine release. Possible risks related to modulation of glycinergic neurotransmission by Tam should be considered when recommending its use in healthy individuals.

Animals↗
PubMed2003

Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.

Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.

Antineoplastic Agents, Hormonal↗
PubMed2000

Hormonal and Nonhormonal Therapies for the Postmenopausal Woman: What is the Evidence for Cardioprotection?

Despite biologically plausible mechanisms whereby estrogen may confer cardioprotection as well as observational data suggesting cardiovascular benefit, data from the sole randomized controlled clinical outcomes trial reported on the benefit of hormone use. A trend was observed in the Heart and Estrogen/progestin Replacement Study (HERS) of an early increase in coronary events with possible late benefit, and in a recent angiographic trial, the Estrogen Replacement and Atherosclerosis trial (ERA) where no benefit was seen. Furthermore, selective estrogen receptor modulators may enable dissociation of estrogen risks and benefits; the selective estrogen replacement modulator raloxifene is under study in a large randomized clinical outcomes trial entitled the Raloxifene Use for the Heart trial (RUTH). (c) 2000 by CVRR, Inc.

Journal Article↗
PubMed2002

Terpenoids found in the umbelliferae family act as agonists/antagonists for ER(alpha) and ERbeta: differential transcription activity between ferutinine-liganded ER(alpha) and ERbeta.

Phytoestrogens are assumed to affect the endocrine system of animal species similarly to other man-made endocrine disrupters and to exert their effects through estrogen receptors, specifically ER(alpha) and ERbeta. However, these molecular mechanisms are not fully understood. In this study, 19 phytochemicals were surveyed for agonist and antagonist activities of ER(alpha) and ERbeta using an ERE-luciferase reporter assay. The results showed that ferutinine is an agonist for ER(alpha) and an agonist/antagonist for ERbeta, tschimgine is an agonist for both ER(alpha) and ERbeta, and tschimganidine is an agonist for only ER(alpha). Ferutinine and tschimganidine are sesquiterpenoids, and tschimgine is a monoterpenoid derived from the Umbelliferae family. A competitive binding assay showed that ferutinine has higher binding affinities than tamoxifen for both ERs. Co-transfections of coactivators such as SRC-1, TIF2, AIB1, and TRAP220 in 293T cells and use of the luciferase assay revealed that TRAP220 failed to enhance the transcription mediated by ERbeta in the presence of ferutinine. Moreover, a GST pull-down assay showed that TRAP220 marginally bound to ERbeta ligand binding domain in the presence of ferutinine. These results suggest that the conformation of ferutinine-liganded ERbeta is difficult for TRAP220 to recognize. Taken together, this suggests that some terpenoids can modulate estrogen signaling as ER subtype-selective phytoestrogens similar to SERMs (selective estrogen receptor modulators).

Apiaceae↗