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PubMed1993

Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens.

The effects of equimolar doses of the triphenylethylene antiestrogens tamoxifen and toremifene on female Sprague-Dawley rat liver were studied in a 52-week toxicity study which included a 13-week recovery period. Liver tumors were found in four out of five rats at the highest dose level of tamoxifen (45 mg/kg per day) after 52 weeks of dosing, and these appeared to be hepatocellular carcinomas in three rats. After the 13-week recovery period all surviving rats in the highest tamoxifen dose group had large liver tumors (diameter up to 2 cm) which appeared to be hepatocellular carcinomas in five out of six rats. No tumor was observed in the toremifene-treated rats (48 mg/kg per day) either after 52 weeks of dosing or after the recovery period. Electron microscopic morphometric analysis after 52 weeks of dosing revealed that at the tamoxifen high dose level, the volume densities of the peroxisomes, mitochondria, and residual bodies were elevated in the nonneoplastic hepatocytes of the rats. In the neoplastic hepatocytes of the tamoxifen-treated rats the volume density of nuclei was slightly elevated. The slight proliferation of peroxisomes and mitochondria might be related to tumor development in the tamoxifen treated rats.

Animals↗
PubMed2002

Activation of Maxi Cl(-) channels by antiestrogens and phenothiazines in NIH3T3 fibroblasts.

The identification of alternative estrogen actions has been accumulating steadily over the past two decades. Typically, these novel actions are not directly related to nuclear transcriptional events but related to the interaction of estrogens with sites present at plasma membrane or cytosolic locations. These alternative effects, widely known as non-genomic effects, range from the modulation of plasma membrane ion channel activity to the regulation of different intracellular signalling cascades. In the present study we have investigated the modulation of a large conductance chloride channel (Maxi Cl(-)) by estrogens, non-steroidal triphenylethylene antiestrogens and phenothiazines in NIH3T3 fibroblasts and the dependence on guanosine triphosphate (GTP) of the Maxi Cl(-) activation. Our data identifies the non-steroidal antiestrogens toremifene and tamoxifen, and the phenothiazines chlorpromazine and triflupromazine as activators of Maxi Cl(-) channels. In contrast, 17 beta-estradiol and cAMP, added prior to the exposure to antiestrogens, prevent channel activation. The pure antiestrogen ICI 182780 did not activate the channel nor prevent its activation by non-steroidal antiestrogens. The activation of Maxi Cl(-) channels by toremifene and tamoxifen required the presence of intracellular nucleotides and was inhibited by the stable analog, GDP beta -S, suggesting the participation of a G-protein in the activation process. Little is known about the physiological relevance of Maxi Cl(-) channels. However, that fact that its regulation by estrogens and antiestrogens is shared by different cell types might imply a common role which needs to be identified.

3T3 Cells↗
PubMed1999

Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells.

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and an important prognostic factor in breast cancer. Hypoxia is an important inducer of VEGF expression but less is known of the role of hormones in VEGF regulation. We have studied the regulation of VEGF, VEGF-B, VEGF-C, and VEGF-D mRNAs in human MCF-7 and mouse S115 breast carcinoma cells stimulated by estrogens and androgens, respectively. VEGF, VEGF-B, and VEGF-C were expressed in both cell lines, whereas VEGF-D was expressed only in S115 cells. Addition of estradiol (E2) caused a biphasic increase of VEGF mRNA in MCF-7 cells and led to accumulation of the VEGF protein in the culture medium. The VEGF-B mRNA was not affected, while a decrease occurred in VEGF-C mRNA. Similarly, testosterone upregulated the expression of VEGF mRNA in the S115 cells. Experiments with actinomycin D and cycloheximide suggested that estrogen induction of VEGF mRNA is dependent on the synthesis of new mRNA and increased mRNA half-life. The antiestrogen ICI 182.780 inhibited E2 stimulation of VEGF, suggesting that the effect was mediated by the estrogen receptor. In contrast, the antiestrogens tamoxifen and toremifene which inhibit MCF-7 cell growth in vivo and in vitro did not inhibit estrogen effect but induced VEGF mRNA expression when used alone. The antiandrogen cyprosterone acetate inhibited T induction of VEGF mRNA in S115 cells, thus suggesting that activation of androgen receptor must be involved in the increase of VEGF mRNA. Our results suggest that both estrogen and androgen stimulate the expression of VEGF by increasing gene transcription and mRNA stability. In addition, the antiestrogens tamoxifen and toremifene also increased VEGF expression. Estrogen and androgen induction of VEGF expression and promotion of new vessel formation may be an important paracrine mechanism by which these hormones contribute to the early phase of tumor growth of hormonal cancer.

Animals↗
PubMed2001

Delayed effects of tamoxifen in hepatocarcinogenesis-resistant Fischer 344 rats as compared with susceptible strains.

The anti-oestrogenic drug tamoxifen has been under investigation as a breast cancer chemopreventive agent for at least a decade. However, its use for this purpose is still debatable since it is able to induce liver tumours in rats via a mechanism involving metabolic activation to a DNA adduct-forming electrophilic intermediate. The metabolic activation and adduct-forming properties of tamoxifen are now well characterized but less is known about its ability to induce hepatic cell proliferation, which is also essential for the carcinogenic process. The effects of tamoxifen on liver weight and cell proliferation were compared in female Fischer 344 (F344), Wistar and Lewis rats given the drug in the diet for up to 26 weeks. The onset and duration of hepatic cell proliferation varied between the strains of rat. In Wistar and Lewis but not F344 rats there was a marked increase in hepatocellular proliferation during the first 4 weeks of tamoxifen administration. In the Wistar strain this was associated with an increase in DNA adduct levels; no such increase was observed in the F344 strain. The onset of the proliferative response was delayed until the 13 week time point in the F344 strain. By the 13 and 26 week time points, cell proliferation in tamoxifen-treated Wistar and Lewis rat liver had returned to normal, but the amount of apoptotic activity in these livers was elevated. This suggests that excess cells generated during the proliferative phase of tamoxifen treatment were being eliminated by apoptosis. In the F344 strain, however, increased proliferative activity was associated with relatively low apoptotic activity at the 26 week time point, suggesting that the delayed proliferative response had yet to be balanced by apoptotic deletion. This is consistent with the fact that tamoxifen-induced hepatocellular tumours develop very late, towards the end of the lifespan, in this strain. The cell proliferative activity of tamoxifen in the Wistar rat liver was compared with that of a non-mutagenic analogue, toremifene. Tamoxifen induced increased cell cycle activity in the livers of rats following gavage dosing at all sampling times (1-12 weeks), whereas toremifene had no effect on the incidence of cycling in hepatic cells, demonstrating that the hepatic cell proliferation is not a general response to anti-oestrogen treatment. These observations suggest that the rate of promotion of liver tumours by tamoxifen is a function of the rate, time of onset and duration of increased cell replication. The susceptibility of rat strains to the hepatocarcinogenic effects of tamoxifen appears to depend upon the balance between initiation via DNA adduct formation, promotion via increased cell proliferation and cell deletion via apoptosis. Our findings suggest that an early proliferative response to tamoxifen is important in this process.

Animals↗
PubMed1988

Comparative double-tracer whole-body autoradiography: uptake of 11C-, 18F- and 3H-labeled compounds in rat tumors.

The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined in tumors and some selected tissues by positron emission tomography (PET). The uptake rate between fluorodeoxyglucose and thymidine in the mammary tumor was five times higher than the ratio in the Walker tumor. The corresponding figure for FDG/methionine was four times. Thymidine, compared with methionine, was twice as efficient. Thus, the mammary tumors were best imaged with FDG or thymidine. The non-steroid antiestrogen toremifene was taken up in very low amounts by these tumors. By DTWBA, experimental tumors may serve as their own control.

Animals↗
PubMed1993

Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites.

The ability of the anti-oestrogens tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites to modify doxorubicin (dox) toxicity to intrinsically resistant and multidrug resistant cell lines was compared, using human breast and lung cancer, and Chinese hamster ovary cell lines. The anti-oestrogens significantly enhanced dox toxicity to multidrug resistant, P-glycoprotein-positive cell lines, but did not affect toxicity to intrinsically resistant, P-glycoprotein-negative cells. Modification was observed at clinically achievable anti-oestrogen concentrations. Toremifene and tamoxifen would therefore appear to be good candidates for in vivo studies as MDR modulating agents in selected patients with P-glycoprotein-positive tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Toxicity of antiestrogens.

The object of this article is to review briefly the preclinical and clinical safety of some antiestrogens. Tamoxifen, toremifene, droloxifene, and idoxifene are polyphenylethylene antiestrogens, whereas the pure antiestrogen, ICI 182,780 or faslodex, as well as raloxifene, is of a different structure. Tamoxifen has been shown to be genotoxic in several studies. It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5 a cells in vitro. Tamoxifen also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow. Toremifene has also shown to be genotoxic, but to a far lower extent, by inducing micronuclei in MCL-5 a cells in vitro and by inducing aneuploidy in rat liver in vivo. Tamoxifen has been shown to be hepatocarcinogenic in the rat in at least four independent long-term studies. The initiation of tumors in the rat is the result of metabolic activation by cytochrome P450 isoenzymes to an electrophile(s) that binds irreversibly to DNA. The other antiestrogens have not been shown to be carcinogenic in rodents. In several independent clinical studies, the risk of endometrial cancer has increased among tamoxifen-treated women. After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufficient evidence to show that tamoxifen is a class I human carcinogen. The increased risk for endometrial cancer occurs predominantly among women who are 50 years old or older and who have been treated with tamoxifen. It is not yet clear whether the uterine tumor formation is a result of genetic mechanisms, analogous to those seen in the rat liver or due to the estrogen agonist action of tamoxifen. However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans.

Age Factors↗
PubMed2001

The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer.

In this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine - 3.0% vs. + 1.2% (P< 0.001), but not in femoral neck - 0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P< 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.

Aged↗
PubMed2000

Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Prospective evaluation of estrogen receptor-beta in predicting response to neoadjuvant antiestrogen therapy in elderly breast cancer patients.

It has been proposed that knowledge of estrogen receptor beta (ER-beta) expression may refine estrogen receptor alpha (ER-alpha) predictivity of response to endocrine therapy. We challenged this hypothesis in ER-alpha-positive breast cancers subjected to preoperative antiestrogen treatment. Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months). ER-alpha and ER-beta (ERs) mRNA was determined by semiquantitative RT-PCR, before (on core needle biopsy) and after (on surgical specimens) neoadjuvant treatment. Study end points included: (1) relation between treatment response and ER mRNA expression; and (2) changes in ER expression after treatment. The response was clinically assessed as tumor size change at the end of the preoperative treatment. ER mRNA expression was assessable before and after treatment in 38 and 20 cases respectively. ER-beta was co-expressed with ER-alpha at variable levels and significantly correlated only with progesterone receptor (P = 0.0285). Objective clinical response, including patients with minor change (> or =25-<50% tumor shrinkage after treatment), was documented in 68.4% of cases and was independent of ER-beta levels or changes. ER-alpha levels were higher in tumors from patients in complete remission than in those from women achieving partial response or minor change compared with non-responsive patients (median expression values: 801 versus 516 versus 320 arbitrary units) and were consistently down-regulated by preoperative treatment. We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response.

Aged↗
PubMed1999

Selective estrogen receptor modulators: a look ahead.

Selective estrogen receptor modulators (SERMs) are structurally diverse compounds that bind to estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. They are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or are in clinical development, including triphenylethylenes (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Tamoxifen was recently shown to decrease the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis and fragility fractures, also has favourable effects on bone mineral density, serum lipids and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer post-menopausal women many of the advantages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by raloxifene, also eliminate the concerns over endometrial stimulation that were not addressed by first generation SERMs. The clinical success of SERMs has set the stage for a variety of drug therapies based on selective modulation of nuclear receptor activity.

Estrogen Antagonists↗
PubMed1994

[Breast cancer--tamoxifen and tamoxifen analogues for the treatment of breast cancer].

Tamoxifen (20-40 mg/day) has been widely used for the treatment of breast cancer and is recognized as a useful antiestrogen. A 40 mg/day dose of toremifene showed comparable efficacy, safety and usefulness to a 20 mg/day dose of tamoxifen in the double-blind comparative study with tamoxifen. Furthermore, high-dose toremifene (120 mg/day) was effective on the tamoxifen-failed breast cancer patients. Although droloxifene (3-hydroxytamoxifen) showed efficacy and safety in phase I and phase II studies, this trial has regretably been ineffective in Japan. In phase I and early phase II trials in Japan, the safety and efficacy of TAT-59 was demonstrated and a 20 mg/day dose was moderate. Tamoxifen analogues including their metabolites are expected to act effectively on tamoxifen-resistant, low estrogen receptor levels or estrogen receptor-negative tumors by mechanisms of action different from tamoxifen.

Binding, Competitive↗
PubMed1997

Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro.

Since estrogens play a predominant role in the development and growth of human breast cancer, antiestrogens represent a logical approach to the treatment of this disease. The present study compares the effects of the novel nonsteroidal anti-estrogen EM-800 and related compounds with those of a series of anti-estrogens on basal and 17 beta-estradiol (E2)-induced cell proliferation in human breast cancer cell lines. In the absence of added E2, EM-800 and related compounds failed to change basal cell proliferation, thus showing the absence of intrinsic estrogenic activity in the ER-positive T-47D, ZR-75-1 and MCF-7 cell lines. The stimulation of T-47D cell proliferation induced by 0.1 nM E2 was competitively blocked by a simultaneous incubation with EM-652, EM-800, OH-tamoxifen, OH-toremifene, ICI 182780, ICI 164384, droloxifene, tamoxifen and toremifene at apparent Ki values of 0.015, 0.011-0.017, 0.040-0.054, 0.043, 0.044, 0.243 and 0.735 nM, approx. 10 nM and > 10 nM, respectively. Similar data were obtained in ZR-75-1 and/or MCF-7 cells. Moreover, EM-652 was 6-fold more potent than OH-Tamoxifen in inhibiting the proportion of cycling MCF-7 cells. Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells.

Benzopyrans↗
PubMed1995

Pharmacokinetics and metabolism of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in mammary tumors of antiestrogen-treated rats.

Attempts are being made to evaluate 2-[18F]fluoro-2-deoxy-D-glucose (FDG) as a noninvasive marker of therapy response in malignant tumors. We studied rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinomas by measuring the differential absorption ratio (DAR) and the metabolites of FDG in tumor homogenates. Half the rats were treated with the antiestrogen toremifene for 14 days and half were untreated. The histology of the tumors was studied by morphometry. The animals were killed 15, 45 or 240 min after injection. Regardless of whether the rats received toremifene or not, the fractional change in tumor volume correlated better with the DAR at 15 min [r = 0.284 (untreated) and r = 0.721 (treated)] and at 240 min [r = 0.932 (untreated)], than at 45 min [r = -0.137 (untreated) and r = 0.265 (treated)]. Inverse relations were found for the fraction of unmetabolized FDG and change in tumor volume [r = 0.070 (45 min) and r = -0.872 (240 min) for untreated tumors and r = -0.963 (15 min) and r = -0.715 (45 min) for treated tumors]. The DAR and the fraction of unmetabolized FDG correlated also [r = -0.420 (15 min), r = -0.647 (45 min) and r = -0.976 (240 min) for untreated tumors, and r = -0.963 (15 min) and r = -0.213 (45 min) for treated tumors]. No significant therapy-induced morphometrical changes were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer.

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium due to liganded ER activating target genes in these different types of cell. Several novel anti-estrogen compounds have been developed which have a reduced agonist profile on breast and gynaecological tissues. These compounds offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for two groups of agents: the selective estrogen receptor modulators (SERMs), further divided into "tamoxifen-like" (e.g. toremifene, droloxifene and idoxifene) and "fixed ring" compounds (e.g. raloxifene, arzoxifene and EM-800), and the selective estrogen receptor down-regulators (SERDs; e.g. fulvestrant (ICI 182780), SR 16234 and ZK 191703) also termed "pure anti-estrogens". In phase II trials in tamoxifen-resistant metastatic breast cancer the SERMs show low objective response rates (range 0-15%), suggesting cross resistance with tamoxifen. Randomized phase III trials for toremifene and idoxifene in over 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the "fixed ring" SERMs and it remains unclear whether any clinical advantage exists for the "fixed ring" SERMs over tamoxifen as first-line therapy. The main advantage for SERMs such as tamoxifen and raloxifene probably remains in early-stage disease (adjuvant therapy or prevention). Fulvestrant and the other SERDs have a high affinity for the estrogen receptor (ER) compared to tamoxifen, but none of its agonist activities. Of the SERDs, only fulvestrant has entered the clinic and this new agent is showing promising clinical activity in the treatment of advanced breast cancer. Recently published phase III studies have shown fulvestrant to be at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or progressed on prior endocrine therapy. Surprisingly, however, in a phase III trial versus tamoxifen for the first-line therapy of advanced breast cancer fulvestrant did not attain the requirements for equivalence to tamoxifen, and in terms of time-to-treatment failure was inferior (5.9 versus 7.8 months for fulvestrant and tamoxifen, respectively; P=0.029). Future clinical studies will evaluate fulvestrant in the neoadjuvant setting together with its optimal sequencing in relation to tamoxifen and other endocrine therapies in advanced disease.

Antineoplastic Agents, Hormonal↗
PubMed1998

Inhibition of ligand-gated cation-selective channels by tamoxifen.

The nonsteroidal antioestrogen tamoxifen has been shown to block a number of voltage-gated cation-selective channels but its effect on ligand-gated cation-selective channels has not been studied. We have investigated the action of tamoxifen and the related derivative toremifene on ligand-gated cationic nicotinic acetylcholine and 5-HT3 receptor channels. Tamoxifen and toremifene both inhibited cationic currents of adult-type human muscle nicotinic acetylcholine receptors expressed in Xenopus oocytes with similar IC50 values of 1.2 +/- 0.03 microM (nH = 0.84 +/- 0.02) and 1.2 +/- 0.1 microM (nH = 1.1 +/- 0.1), respectively. Tamoxifen could also block native 5-HT3 receptors in NG108-15 neuroblastoma/glioma hybrid cells with IC50 = 0.81 +/- 0.15 microM and nH of 1.3 +/- 0.3. The characteristics of block by tamoxifen at the 5-HT3 receptor were voltage- and use-independent. The inhibition of the 5-HT-evoked currents were not overcome by increasing concentrations of 5-HT consistent with a noncompetitive mechanism of block.

Animals↗
PubMed1998

DNA cleavage and 8-hydroxydeoxyguanosine formation caused by tamoxifen derivatives in vitro.

DNA damage caused by tamoxifen and its derivatives was examined by estimating the conversion of supercoiled pUC18 plasmid DNA to linear form by means of agarose gel electrophoresis. N-Desmethyltamoxifen induced DNA cleavage and its effect was enhanced by the addition of reducing agents such as dithiothreitol, NADPH and 2-mercaptoethanol. 4-Hydroxytamoxifen itself had little effect, but the cleavage was slightly enhanced by the addition of reducing agents. DNA damage was higher with alpha-hydroxytoremifene than with alpha-hydroxytamoxifen, which had a prominent effect only at high concentration. The cleavage by alpha-hydroxy derivatives were not enhanced by reducing agents. No damage was induced by tamoxifen, toremifene, 3-hydroxytamoxifen or N-desmethyltoremifene. The DNA cleavage by N-desmethyltamoxifen was inhibited by the addition of EDTA, mannitol, sodium azide, methionine, catalase and superoxide dismutase. The formation of 8-hydroxy-2'-deoxyguanosine was also examined with calf thymus DNA in vitro. A slight increase of its level was found with 4-hydroxytamoxifen in the presence of dithiothreitol and also with N-desmethyltamoxifen in the presence of NADPH, but alpha-hydroxytoremifene and alpha-hydroxytamoxifen were ineffective. These experimental data suggest that among metabolites of tamoxifen, N-desmethyltamoxifen and probably also 4-hydroxytamoxifen cause oxidative DNA damage in which redox cycling is involved. The DNA damage by alpha-hydroxytoremifene appears to involve a different mechanism from that by N-desmethyltamoxifen. Tamoxifen and toremifene are possibly metabolized to the forms contributing to DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

SERMs: current status and future trends.

Selective estrogen receptor modulators, or SERMs, are a class of compounds that can act as estrogen receptor (ER) agonists in some tissues while acting as ER antagonists in others. SERMs are being evaluated and used to treat and prevent such diseases as breast cancer, osteoporosis, and cardiovascular disease. Currently, three primary SERMs are used clinically, which include tamoxifen, toremifene (triphenylethylenes), and raloxifene (a benzothiophene). Tamoxifen and toremifene have beneficial effects on bone and serum lipids, and are currently used to treat breast cancer. Both have stimulatory effects on the uterus. Raloxifene, indicated for the treatment and prevention of osteoporosis, also has beneficial effects on bone and serum lipids, but does not stimulate the uterus. All three are associated with venous thromboembolism and hot flashes. New SERMs to treat and prevent breast cancer, osteoporosis, and cardiovascular disease are undergoing clinical development, including idoxifene, droloxifene, ospemifene, lasofoxifene, arzoxifene, and MDL 103,323.

Animals↗