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PubMed1999

Correlation of DNA adduct levels with tumor incidence: carcinogenic potency of DNA adducts.

The quantitative relationship between DNA adducts and tumor incidence is evaluated in this review. All available data on DNA adduct levels determined after repeated administration of a carcinogen to rats or mice have been compiled. The list comprised 27 chemicals, of all major structural classes of carcinogens. For the correlation with tumor incidence, the DNA adduct levels measured at the given dose were normalized to the dose which resulted in a 50% tumor incidence under the conditions of a 2-year bioassay (TD50 dose). In rat liver, the calculated adduct concentration 'responsible' for a 50% hepatocellular tumor incidence spanned from 53 to 2083 adducts per 108 nucleotides, for aflatoxin B1, tamoxifen, IQ, MeIQx, 2,4-diaminotoluene, and dimethylnitrosamine (in this order). In mouse liver, the respective figures were 812 to 5543 adducts per 108 nucleotides, for ethylene oxide, dimethylnitrosamine, 4-aminobiphenyl, and 2-acetylaminofluorene. The observed span (40-fold in rats, 7-fold in mice) reflects differences between the various DNA adducts to lead to critical mutations. If additional carcinogens fit in with this astonishingly narrow range, the measurement of DNA adduct levels in target tissue has the potential to be not only an exposure marker but an individual cancer risk marker. For toremifen and styrene, low levels of DNA adducts were detected in rat liver at the end of a negative long-term bioassay. This shows that the limit of detection of DNA adducts can be well below the limit of detection of an increased tumor incidence. For a cancer risk assessment at low levels of DNA damage, treatment-related adducts must be discussed in relation to the background DNA damage and its inter- and intraindividual variability.

Animals↗

PubMed2002

The impact of hormonal treatments on quality of life of patients with metastatic breast cancer.

BACKGROUND: The concept of quality of life (QOL) increasingly has been used to assess health-related outcomes associated with a specific disease or its treatment, especially in patients with incurable tumors, such as metastatic breast cancer (MBC). Hormonal therapy (HT) is often used to treat hormone receptor-positive MBC, with the primary treatment goal of reducing both disease burden and patient suffering. OBJECTIVE: This article reviews the instruments used to assess QOL in patients with breast cancer, the adverse effects of HTs, and the clinical trials that assess QOL in patients with MBC receiving various HTs. METHODS: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstacts (2001 and 2002). The following search terms were used: quality of life, breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, and megestrol acetate. CONCLUSIONS: QOL assessment following MBC treatment has become an important indicator of treatment effectiveness, and numerous clinical trials have studied the impact of HT on QOL. In general, the older HTs, such as the progestins and selective estrogen receptor modulators (SERMs), produce more adverse effects than do the newer HTs, such as the aromatase inhibitors (AIs) and estrogen receptor (ER) antagonists. QOL data regarding tamoxifen, a SERM associated with a high incidence of vasomotor symptoms and vaginal discharge, are limited, although tamoxifen has not been associated with significant psychological distress when administered as a chemopreventive or adjuvant MBC therapy in clinical trials. QOL studies comparing the third-generation AIs with tamoxifen or megestrol acetate show that the AIs produce a more favorable QOL, probably because these agents target the aromatase enzyme, which results in a lower incidence of thromboembolism and vaginal bleeding. Although QOL studies of the ER antagonist fulvestrant have not been conducted, several attributes of this new HT may contribute to the retention of a good QOL in patients with MBC. A variety of QOL-assessment tools to measure the impact of HTs on patients with MBC are available. Clinical trial data regarding QOL in patients with MBC receiving HT will be useful for both clinicians and patients in evaluating treatment options and developing treatment strategies.

Antineoplastic Agents, Hormonal↗

PubMed2002

Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer.

BACKGROUND: Hormonal therapy (HT) is an important consideration in the management of postmenopausal women with metastatic breast cancer. Despite the fact that the advanced-stage disease is virtually incurable, HTs can offer patients disease control equivalent to that of chemotherapy, but with improved quality of life (QOL). Knowledge of the estrogen and progesterone receptor status, as well as other clinical factors, allows for selection of patients who are most likely to benefit from HT. Disease that becomes refractory to an initial HT may respond to another agent or class of HTs. Thus, HTs are generally administered sequentially, delaying the need for cytotoxic chemotherapy, which often reduces QOL. Optimal sequencing is thus one of the more important facets of HT. Prior to the release of a number of newer agents, tamoxifen had been considered as initial HT. At present, more agents exist, including the aromatase inhibitors, progestins, and the estrogen receptor antagonist fulvestrant. OBJECTIVE: This article reviews key trials evaluating the use of sequential HTs. METHODS: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Results of Phase III studies have shown many of these agents to be equivalent or superior to tamoxifen and can be used initially to treat patients who either have failed tamoxifen therapy or may be unable to tolerate some of the toxicities associated with tamoxifen. For example, the aromatase inhibitors have been shown to be highly active and tolerable in postmenopausal women with breast cancer who have failed tamoxifen therapy or who are naive to HT. Other clinical trials have demonstrated the efficacy of fulvestrant in patients with metastatic breast cancer who are tamoxifen-resistant, and have shown fulvestrant to be at least as effective as anastrozole in tamoxifen-resistant patients. CONCLUSIONS: Although the optimum sequence of HTs remains controversial, using the newer agents as initial or subsequent therapy should improve QOL and may improve overall survival.

Antineoplastic Agents, Hormonal↗

PubMed2001

Anti-oestrogenic drugs and endometrial cancers.

Tamoxifen is one of the most effective drugs to be used in the treatment of women with breast cancer and as a chemopreventive agent in women 'at risk' from this disease. Tamoxifen can be regarded as a paradigm for a new range of selective oestrogen receptor modulators that include toremifene, used in the treatment of metastatic breast cancer and raloxifene, presently approved for use in postmenopausal women for the treatment of osteoporosis. Tamoxifen treatment of women leads to a small increase in the incidence of endometrial cancers. It is important to understand the mechanism for this side effect in order to predict the likely human risk for other drugs of this class. Two such mechanisms have been proposed: (1) conversion of the drug to electrophilic metabolites that damage cellular DNA; and (2) an oestrogen agonist action on the uterus, promoting endogenous lesions. In rats, long-term tamoxifen treatment results in liver cancer via a genotoxic mechanism. However, it seems most likely that, in women treated with tamoxifen, endometrial cancer is related to an oestrogen agonist effect of this drug, promoting uterine cell proliferation.

Animals↗

PubMed1998

DNA binding of tamoxifen and its analogues: identification of the tamoxifen-DNA adducts in rat liver.

DNA binding of tamoxifen and some structurally-related drugs (toremifene, clomiphene, triparanol and raloxifene) in rat liver was studied using the 32P-postlabelling method. As only tamoxifen was shown to form high levels of DNA adducts, the identity of these adducts was studied. Recently, we have identified by mass spectroscopy the two main tamoxifen adducts in rat liver DNA as the N-desmethyltamoxifen and tamoxifen adducts of N2-deoxyguanosine in which the linkage is through alpha-carbon in the tamoxifen structure. Minor adducts were identical to different diastereomers of alpha-(N2-deoxyguanosinyl)tamoxifen and of alpha-(N6-deoxyadenosinyl)tamoxifen. Altogether these adducts accounted for at least 95% of adducts formed in vivo, implicating that the alpha-hydroxylation of the ethyl group is the major activation pathway for DNA adducts.

Animals↗

PubMed1999

Quantitative analysis of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol in human plasma using high-performance liquid chromatography.

A highly sensitive and precise high-performance liquid chromatography (HPLC) assay was developed and validated for the quantitation of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl) phenoxy]ethanol (FC-1271a) in human plasma. Plasma samples (1.0 ml) containing FC-1271a and internal standard (toremifene citrate; Farestono) were extracted using a 2% 1-butanol, 98% hexane solution with an extraction efficiency of >97%. Samples were reconstituted in methanol, irradiated with high intensity ultraviolet light (254 nm) for 1 min, and injected onto a C18 reverse phase column. Samples were eluted isocratically at a flow-rate of 0.5 ml/min with a mobile phase consisting of 6.5% water and 0.5% triethylamine in methanol. The fluorescence of photochemically activated compounds was detected using a fluorometer set at an excitation wavelength of 266 nm and emission wavelength of 370 nm. Under these assay conditions, standard calibration curves were linear through a concentration range of 10-400 ng/ml. In summary, we have developed and validated an HPLC assay to quantitate FC-1271a in human plasma.

Animals↗

PubMed2001

In vitro and in vivo biologic effects of Ospemifene (FC-1271a) in breast cancer.

Ospemifene (FC-1271a) is a novel selective estrogen receptor modulator under development for osteoporosis prevention. In the present paper, we examine both the in vitro and in vivo effects of FC-1271a in breast cancer models. In vitro, the growth inhibitory effects of FC-1271a and its main metabolite are investigated in MCF-7 and MDA-MB-231 human breast cancer cells at doses ranging from 0.1 to 10 microM. Modulation of pS2 expression, an indicator of estrogen activity, was also examined in all experiments using reverse transcription-polymerase chain reaction. In vivo, the effects of treatment with 10, 25, 50, or 100 mg/kg FC-1271a on MCF-7 and MDA-MB-231 human tumor xenografts in athymic, ovariectomized mice were determined. For MCF-7 cells, FC-1271a and its main metabolite, toremifene VI (TOR VI) displayed anti-estrogenic effects in vitro as shown through growth inhibition and decreased expression of pS2. Treatment with FC-1271a in vivo inhibited MCF-7 tumor growth, compared with control (P< or =0.05). FC-1271a and TOR VI did not inhibit the growth of MDA-MB-231 cells in vitro, and no clear effects of FC-1271a treatment were seen on MDA-MB-231 tumor growth in vivo. In conclusion, FC-1271a appears to exert anti-estrogenic effects dependent on estrogen receptor positivity in vitro and in vivo on the growth of MCF-7 cells.

Animals↗

PubMed1998

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors.

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.

Androgens↗

PubMed2003

Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers.

Significant progress has been made in understanding the biology of urothelial and kidney cancers. Approaches to advanced urothelial cancer include dose intensification, reducing toxicity in unfit or elderly patients, doublet and triplet combination chemotherapy and sequential regimens. Promising new chemotherapeutic agents such as the epothilones, pemetrexed (Alimta), topoisomerase inhibitors and vinflunine act at different phases of the cell cycle and on folate metabolism. New agents that are combined with chemotherapy in urothelial cancer include the farnesyl transferase inhibitors and growth factors receptor inhibitors. Renal cell carcinoma (RCC) is particularly resistant to cytotoxic agents, although a gemcitabine/fluorinated pyrimidine combination may have modest but real clinical benefit. In metastatic RCC, new biologic and targeted therapies include anti-angiogenesis agents such as anti-vascular endothelial growth factor (VEGF) antibody and thalidomide, as well as toremifene, CCI-779 and allogeneic stem cell transplantation. Metastatic urothelial and renal cell cancers continue to be the clinical trial focus of many novel agents. The molecular biology of these diseases is being unravelled and as knowledge accumulates, our ability to target these cancers will continue to increase.

Angiogenesis Inhibitors↗

PubMed1999

SERM Drugs for the Prevention of Osteoporosis.

Although estrogens have proved useful in the prevention and treatment of osteoporosis, their side effects (for example, those on breast and endometrial cancer) are worrying to patients and physicians alike. Therefore, selective estrogen receptor modulator (SERM) drugs have been developed for use in their stead. The triphenylethylene drug tamoxifen proved to be protective against bone loss, but had side effects on uterus similar to those of natural estrogens. The tamoxifen derivative toremifene has less effect on bone. Further derivatives of tamoxifen (droloxifene, idoxifene) can be expected to act like tamoxifen when approved for clinical testing. The non-steroidal benzothiophene derivative, raloxifene, is the best SERM available thus far. It does not increase the incidence of endo-metrial cancer; in addition, like tamoxifen, it has the potential to prevent breast cancer, but has a better profile in its actions on bone (for example, it reduces the vertebral fracture rate more effectively than tamoxifen). Unlike estrogen, it decreases blood triglicerides as well as cholesterol.

Journal Article↗

PubMedDate not supplied

Selective estrogen receptor modulators (SERMs): A first step in the development of perfect hormone replacement therapy regimen.

Until 1986, our understanding of estrogen receptor (ER) action was based on information derived from in vitro biochemical analyses and in vivo correlations. With the cloning of the human ER cDNA, the reconstitution of ER responsive transcription units in heterologous cells has permitted the genetic dissection of the ER signal transduction pathway. The recent discovery of ER beta and a multitude of adaptor proteins (coactivators and corepressors) has expanded the potential explanation for tissue-selective activities. The current concept of ER action includes a rheostat-like action of the receptor due to conformational changes in the ligand receptor complex that depend on the nature of the bound ligand. This conformational change also determines subsequent adaptor protein interactions. Recognition of the tissue-specific activities of tamoxifen, the first selective ER modulator (SERM), led to the development of new SERMs (raloxifene and toremifene) with greater tissue selectivities. A knowledge of the key adaptor proteins expressed within each ER target cell will allow mechanism-based screening of selective ER modulators. These future "designer estrogens" of the next millennium will be used for specific applications in the central nervous, cardiovascular, bone and reproductive systems.

Estrogen Replacement Therapy↗

PubMed2026

Spectral-Proteomic Integration Analysis (SPIA) Deciphers Molecular Trajectories of Breast Cancer and Enables Multitarget Therapeutic Assessment.

Raman spectroscopy and mass spectrometry-based proteomics offer deeply complementary yet largely disconnected views of cancer biology: the former provides a label-free, real-time biochemical phenotype, while the latter delivers a quantitative inventory of specific protein effectors. Bridging this gap remains a fundamental challenge in analytical biomedicine. Here, we introduce Spectral-Proteomic Integration Analysis (SPIA)─a novel, data-driven integrative framework that systematically links Raman spectroscopic phenotypes with quantitative proteomic profiles through machine learning and statistical correlation. Using a DMBA-induced rat breast cancer model with and without Toremifene (TOR) intervention, SPIA dynamically maps tumor microenvironment remodeling, capturing progressive collagen deposition and lipid metabolic reprogramming. An SVM classifier trained on Raman spectra achieves exceptional diagnostic accuracy (AUC ≥ 99.0%) and successfully predicts TOR therapeutic response. Proteomic analysis identifies 1,350 differentially expressed proteins, with convergent machine learning feature selection (LASSO, Random Forest, XGBoost) pinpointing core regulators including Luc7l2, Nucb1, Cbx3, and Csnk2a1. Crucially, Spearman correlation analysis between key Raman bands and core DEPs reveals strong, statistically robust associations (median ρ ∼ 0.75 in the 1533-1669 cm-1 region), empirically validating SPIA's core integrative logic. Leveraging this multimodal map, we elucidate a multitarget mechanism for TOR involving concurrent suppression of collagen deposition and correction of aberrant lipid metabolism. SPIA establishes a powerful, generalizable paradigm for integrating phenotypic and molecular data, with broad implications for biomarker discovery, drug mechanism elucidation, and precision oncology.

Animals↗

PubMed2006

Antiestrogens and the formation of DNA damage in rats: a comparison.

Tamoxifen (TAM) has been used as an agent for the treatment and prevention of breast cancer. However, long-term treatment of TAM in women increases the risk of developing endometrial cancer. The secondary cancer may be due to the genotoxicity of TAM. To find safer alternatives, four selective estrogen receptor modulators (SERMs), 4-hydroxytamoxifen (4-OHTAM), toremifene (TOR), raloxifene (RAL), and ICI 182,780, were administered to rats with an equimolar dose of TAM [54 micromol/kg (20 mg/kg)/day, p.o. for 7 days]. To evaluate the genotoxicity of each SERM, the presence of bulky DNA adducts was determined by (32)P-postlabeling/polyacrylamide gel electrophoresis and (32)P-postlabeling/high-performance liquid chromatography. The formation of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) was analyzed as a marker of typical oxidative damage, using liquid chromatography electrospray tandem mass spectrometry. Among the SERMs, bulky DNA adducts were detected in the livers of rats treated with TAM; the total amount of TAM-DNA adducts was 26.1 adducts/10(7) nucleotides. However, with a detection limit of approximately 2 adducts/10(9) nucleotides, no bulky DNA adducts were observed with 4-OHTAM, TOR, RAL, or ICI 182,780. In addition, no significant increase of hepatic 8-oxodG lesions was detected in rats treated with any of the antiestrogens. Therefore, TOR, RAL, and ICI 182,780 are likely to be less genotoxic than TAM.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1996

Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes.

Methadone has become one of the most widely used drugs for opiate dependency treatment. This drug is extensively metabolized by the cytochrome P450 hepatic enzyme family in man, yielding an N-demethylated metabolite that cyclizes spontaneously into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. The specific forms of cytochrome P450 involved in this oxidative N-demethylation were examined in a panel of 20 human liver microsomal preparations previously characterized with respect to their P450 enzyme contents. Methadone was demethylated with an apparent Km of 545 +/- 258 microM (n = 3). The metabolic rates were 745 +/- 574 pmol/(min.mg of protein). This metabolic pathway was strongly correlated with estradiol 2-hydroxylation, testosterone 6 beta-hydroxylation, nifedipine oxidation, erythromycin N-demethylation, and toremifene N-demethylation, all of these monooxygenase activities being supported by P450 3A4. Furthermore, the total P450 3A content of liver microsomal samples, determined by immuno-quantification using a monoclonal anti-human P450 3A4 antibody, was correlated with methadone demethylation (r = 0.72; p < 0.003). Methadone metabolism was 60-72% inhibited either by three mechanism-based inhibitors of P450 3A4 (gestodene, TAO, and erythralosamine) or by four reversible inhibitors of P450 3A (ketoconazole, dihydroergotamine, quercetin, and diazepam with an apparent Ki of 50 microM) and by two nonspecific inhibitors (metyrapone and SKF-525A). Conversely, quinidine (inhibitor of P450 2D6), 7,8-benzoflavone (inhibitor of P450 1A), or sulfaphenazole (inhibitor of P450 2C) did not significantly inhibit, and may even have activated, methadone metabolism. Four heterologously expressed P450 proteins were able to catalyze the N-demethylation of methadone, namely, P450 2C8, P450 2C18, P450 2D6, and P450 3A4. However, referring to their relative liver content, it can be asserted that P450 3A4 is the major enzyme involved in the N-demethylation of methadone on average. Accordingly, caution should be advised in the clinical use of methadone when other drugs are also administered that induce or inhibit P450 3A4, such as rifampicin or diazepam, respectively.

Cytochrome P-450 CYP3A↗

PubMed2003

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.

Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de novo resistance mechanism, whereas a complete loss of ER expression is not common in acquired resistance. Antiestrogen unresponsiveness appears to be the major acquired resistance phenotype, with a switch to an antiestrogen-stimulated growth being a minor phenotype. Since antiestrogens compete with estrogens for binding to ER, clinical response to antiestrogens may be affected by exogenous estrogenic exposures. Such exposures include estrogenic hormone replacement therapies and dietary and environmental exposures that directly or indirectly increase a tumor's estrogenic environment. Whether antiestrogen resistance can be conferred by a switch from predominantly ERalpha to ERbeta expression remains unanswered, but predicting response to antiestrogen therapy requires only measurement of ERalpha expression. The role of altered receptor coactivator or corepressor expression in antiestrogen resistance also is unclear, and understanding their roles may be confounded by their ubiquitous expression and functional redundancy. We have proposed a gene network approach to exploring the mechanistic aspects of antiestrogen resistance. Using transcriptome and proteome analyses, we have begun to identify candidate genes that comprise one component of a larger, putative gene network. These candidate genes include NFkappaB, interferon regulatory factor-1, nucleophosmin, and the X-box binding protein-1. The network also may involve signaling through ras and MAPK, implicating crosstalk with growth factors and cytokines. Ultimately, signaling affects the expression/function of the proliferation and/or apoptotic machineries.

Breast Neoplasms↗

PubMed2001

Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene.

Selective estrogen receptor modulators (SERMs) are a diverse group of compounds that bind with specific, high-affinity binding to the estrogen receptor (ER). Depending on the tissue, SERMs can act as either ER agonists or antagonists. Recent advances in ER biology have provided insight into possible mechanisms by which SERMs elicit these tissue-specific estrogen agonist and estrogen antagonist activities. The estrogen response pathway has been shown to differ among target tissues depending on various tissue and cellular factors, such as the ER subtype, the structure of the bound receptor-ligand complex, and the tissue-specific cellular transcriptional machinery. Clinically available SERMs include clomiphene, tamoxifen and toremifene, which are triphenylethylenes, and raloxifene, a benzothiophene. Raloxifene has estrogen agonist effects on bone, serum lipids, and arterial vasculature, and estrogen antagonist effects in breast and uterus. Clinical trial data for raloxifene is used to illustrate some of the mechanisms by which SERMs exert their tissue-specific estrogen agonist and estrogen antagonist effects. The complex pharmacology surrounding the tissue selectivity of SERMs is discussed.

Clinical Trials as Topic↗

PubMed2005

Urogenital effects of selective estrogen receptor modulators: a systematic review.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) include a relatively large number of compounds, each with different profiles of estrogenic/antiestrogenic actions on the genital tract. The aim of this review was to systematically evaluate all the available data from randomized, controlled studies on the effects of these compounds on pelvic organ prolapse and urinary incontinence. METHODS: Literature searches were performed using three computerized databases to identify the result of all randomized, controlled trials performed with SERMs having any effects on pelvic floor as an outcome. A manual search was performed on all related articles. RESULTS: We have identified only one randomized, placebo-controlled trial specifically designed to assess the effect of raloxifene and tamoxifen on the urogenital tract. Most of the data on genitourinary effects of various compounds derive from either questionnaires or adverse events reported during phase III clinical trials. Both tamoxifen and raloxifene appear to increase the incidence of pelvic floor prolapse in one trial, although this was not apparent from the licensing studies data for either of the drugs. Raloxifene does not appear to increase the incidence of urinary incontinence. Levormeloxifene and idoxifene, on the contrary, were noted to increase uterine prolapse and incontinence during phase III trials that prematurely terminated. No data are available on the genitourinary effect of toremifene and on the newer SERMs currently undergoing phase III trials: basedoxifene, lasofoxifene, and arzoxifene. CONCLUSION: Contrary to their effects in bone, SERMs do not have a class-specific effect on the genitourinary tract. In fact, compounds that are more estrogenic on the uterus such as levormeloxifene and idoxifene also increase the risk of prolapse and incontinence. SERMs can adversely affect the pelvic floor and incontinence but data from urodynamic studies are not yet available. Data on prolapse are contradictory. Given the increased incidence of prolapse and incontinence observed in several licensing trials, more focused research on the effect of these molecules on pelvic floor function is needed.

Clinical Trials as Topic↗

PubMed2006

Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00).

BACKGROUND: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing after aromatase inhibitor (AI) treatment. PATIENTS AND METHODS: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n=70) with AI-responsive disease and group B (n=20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (+/-3) days. RESULTS: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease [SD] for >or=24 weeks) in 28% (90% confidence interval [CI] 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B. CONCLUSIONS: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.

Adult↗