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At least 469 records · Page 26Linked to original sources
PubMed1986

A new triphenylethylene compound, Fc-1157a. II. Antitumor effects.

The antitumor effects of a new antiestrogen, Fc-1157a have been studied in vitro and in vivo. In vitro the effect of Fc-1157a was comparable to that of tamoxifen. The effect was dose-dependent, and at concentrations higher than 10(-6) mol/1 Fc-1157a induced real cell death of the MCF-7 cells. In DMBA-induced mammary cancer in rats Fc-1157a decreased the number of new tumors and inhibited the growth of existing tumors, these effects being statistically highly significant. The ratio of growing tumors to stable and regressing tumors was significantly decreased. Although these effects were slightly stronger with Fc-1157a than with tamoxifen, the difference between these two compounds was not statistically significant. Murine uterine sarcoma, an estrogen receptor-negative tumor, was resistant to tamoxifen, but was statistically significantly inhibited by high doses (100 and 200 mg/kg-1 day-1 for 5 days) of Fc-1157a. The antitumor effects of Fc-1157a are due mainly to the antiestrogenic activity. At high concentrations in vitro and at high doses in vivo Fc-1157a exerts antitumor effects some of which are different from those of tamoxifen and are directed even against estrogen receptor-negative tumors. The exact mechanism of the observed cytolytic effect at high doses is unknown.

Animals↗
PubMed2005

Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells.

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.

Antineoplastic Agents, Hormonal↗
PubMed2006

Determinants of early distant metastatic disease in elderly patients with breast cancer.

BACKGROUND: The purpose of this analysis was to determine predictors of early distant metastasis in elderly breast cancer patients receiving hormonal therapy. METHODS: We analyzed data from 938 patients in the North American Fareston Tamoxifen Adjuvant Trial>or=65 years old to determine predictors of early metastatic disease. RESULTS: The median patient age was 73 (range 65 to 100). With a median follow-up of 34 months, 17 patients (1.8%) developed distant metastases. The median time to distant metastasis was 21 months. On univariate analysis, significant predictors of distant metastatic disease were as follows: progesterone receptor status (P=.032), lymphovascular invasion (P=.020), tumor grade (P=.007), tumor size (P<.01), and number of metastatic nodes (P<.01). On multivariate analysis, only the number of positive nodes (P=.029) remained significant. Patients with >or=4 positive nodes were more likely to develop early metastases than those with 0 to 3 positive nodes (odds ration 20.304; 95% confidence interval 2.777-148.456, P=.003). CONCLUSIONS: Lymph node status in the elderly breast cancer patient treated with hormonal therapy alone is a strong predictor of early distant recurrence.

Aged↗
PubMed2005

Beta-interferon and interleukin-2 prolong more than three times the survival of 26 consecutive endocrine dependent breast cancer patients with distant metastases: an exploratory trial.

Distant metastases from breast cancer are incurable. In endocrine-responsive patients antiestrogens are commonly administered as first and second line therapy. Regrettably, tumor growth becomes resistant to this relatively innocuous therapy. Beta-interferon was unsuccessfully added to tamoxifen to induce estrogen receptor enhancement. In mice, interleukin-2 added to tamoxifen increased their mutual anti-tumor activities. Nevertheless, no effective clinical application has been developed. We started an exploratory clinical trial based on the association of these immunostimulating cytokines with antiestrogens for first line salvage therapy of hormone dependent breast cancer with distant metastases. Twenty-six consecutive breast cancer patients with distant metastases, 23 of which had metastases at multiple sites, were studied for responsiveness to treatment with first line salvage antiestrogen therapy, combined with beta-interferon and interleukin-2 immuno-therapy. Clinical response and survival were compared with that of 30 consecutive historical control patients treated with antiestrogen therapy alone. Controls showed, as expected, a median duration of response, a median survival time after treatment, and after diagnosis of distant metastases, of 16, 31 and 34 months, respectively. After a mean follow-up of 62+/-36 months (range 17-155), the interval times in the non-control patients were 61 (P<0.001), 101 (P<0.000001) and 106 (P<0.000001) months. Two long-term survivors appeared to be cured after 155 and 94 months from the time of diagnosis with multiple bone metastases. Nineteen of the patients treated with beta-interferon and interleukin-2 have survived. Hormone immuno-therapy was given in an outpatient setting and was very well tolerated. These data suggest that immuno-therapy plays an important role in endocrine-dependent metastatic breast cancer.

Breast Neoplasms↗
PubMed2005

Adverse outcome and resistance to adjuvant antiestrogen therapy in node-positive postmenopausal breast cancer patients-The role of p53.

The prognostic and predictive relevance of p53 immunoreactivity is used here as a tentative approach for defining more accurately the benefit of adjuvant hormonal therapy in postmenopausal node-positive breast cancer patients. Ninety-seven postmenopausal patients with axillary lymph node metastasis were treated with an antiestrogen for a period of 3 years after primary surgery and radiotherapy. The p53 status of the primary tumor was assessed by immunohistochemistry and 24% of the samples showed positive expression of p53. Within the average follow-up time of 59 months, disease recurrence was diagnosed in 34 patients (35%). Multivariate analysis showed high clinical stage, negative estrogen receptor status and p53 positivity to be independent prognostic factors predicting both shortened disease-free survival and worse overall survival. p53 immunoreactivity was associated with worse clinical outcome irrespective of hormone receptor status. The data suggest that adjuvant therapy with antiestrogens is insufficient in this patient population with p53-positive tumors.

Aged↗
PubMed2007

Relationship of cellular immunity, cytokines and CRP with clinical course in breast cancer patients with endocrine-dependent distant metastases treated with immunotherapy.

We have reported important benefits and survival with an immunotherapy schedule in patients with endocrine-dependent breast cancer and distant metastases. Here clinical outcome is updated and its correlation with new immunological data is shown. In 32 evaluated breast cancer patients with endocrine-dependent distant metastases treated with a new immunotherapy schedule (cyclic administration of beta-interferon and interleukin-2), cellular immunity, cytokines and CRP were related to the clinical course. Estimated and true 5-10 year overall survival rates from first line antiestrogen and distant metastases were higher than previously reported in a similar population. Interleukin-2 administration was followed by a significant increase in total lymphocytes, CD4+, CD8+, CD16+56+ (NK) cells, IL-6, IL-12, and CRP (from P<0.04 to P<0.000) but no change in IL-10 and TGFbeta1 during clinical benefit. During progressive disease no change was observed in the former parameters, concomitant with a significant increase in IL-10 (P=0.020) and a significant decrease in TGFbeta1 (P=0.023). These findings confirm that cellular immunity is significantly stimulated by IL-2 only during clinical benefit. Furthermore, these results demonstrate that different changes of proinflammatory cytokines, CRP and inhibiting factors are consistent with associated clinical benefit or with disease progression, respectively.

Adult↗
PubMed2004

Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma.

Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor lacking identified natural ligands. We have addressed the requirements for ERRgamma-mediated gene regulation. ERRgamma transactivates constitutively reporter genes driven by ERR response elements (ERREs) or estrogen response elements (EREs). The activation depends on an intact DNA-binding domain (DBD) and activation function-2 (AF2). ERRgamma-mediated transactivation is further enhanced by peroxisome proliferator-activated receptor coactivator-1. Interestingly, ligand-binding domain (LBD) mutations predicted to either enlarge or diminish the putative ligand-binding pocket have no effect on the transcriptional activity implying that ERRgamma activity does not depend on any ligands. Antiestrogens 4OH-tamoxifen (4OHT) and 4-hydroxytoremifene (4OHtor) inhibit the ability of ERR to transactivate ERRE and ERE reporters. In contrast, ERRgamma activates transcription at AP-1 sites in the presence of 4OHT and 4OHtor. Thus, the transcriptional activity of ERRgamma seems not to require ligand binding but is modulated by binding of certain small synthetic ligands.

Binding Sites↗
PubMed2002

Evolving uses of hormonal agents for breast cancer therapy.

BACKGROUND: During the past decade, a number of new hormonal therapies (HTs) have been developed, including the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and estrogen receptor (ER) antagonists. Their uses in breast cancer are continually evolving as new clinical trial results become available. Although tamoxifen, the most widely used HT for breast cancer, was originally approved for and used in the treatment of metastatic breast cancer (MBC), its effectiveness as MBC therapy led to its subsequent assessment and use as adjuvant and risk-reduction therapy for breast cancer. However, tamoxifen is not universally effective in these settings and is associated with infrequent known toxicities such as increased risk of thromboembolism and endometrial cancer; therefore, a search for more effective and more tolerable HTs has evolved. OBJECTIVE: This article reviews the data supporting the use of newer HTs as initial treatment of MBC and their potential use as adjuvant, neoadjuvant, and chemopreventive therapies. METHODS: Articles for inclusion in this manuscript were identified 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, breast cancer guidelines, hormonal therapies, tamoxifen, toremifine, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Recent studies have focused on newer agents as initial and subsequent treatment of MBC, adjuvant or neoadjuvant treatments of breast cancer, and chemopreventive agents in both healthy women and women with a history of ductal carcinoma in situ (DCIS). Results of clinical trials comparing AIs with tamoxifen as first-line MBC treatment show that AIs are as effective as, or more effective than, tamoxifen and are associated with fewer serious adverse events. Tamoxifen remains the gold standard for adjuvant therapy. However, preliminary results of ongoing clinical trials comparing tamoxifen with anastrozole suggest that anastrozole may be the superior agent. Both tamoxifen and the AIs have been shown to be active in the neoadjuvant treatment of breast cancer. Trial results have shown that tamoxifen is effective for breast cancer prevention in patients at high risk of developing breast cancer but who are otherwise healthy, patients with a history of DCIS, and patients with lobular carcinoma in situ. CONCLUSIONS: Although tamoxifen has been the gold standard of HT for breast cancer, results of ongoing trials assessing the newer HTs as initial, neoadjuvant, adjuvant, and chemopreventive therapies may substantially change our current clinical practice patterns.

Anastrozole↗
PubMed2000

Clinico-pharmacological aspects of different hormone treatments.

During the last decade, several new drugs and classes of drugs have become available for breast cancer treatment. Thus, in addition to tamoxifen we have got several new selective oestrogen receptor modulators (SERMs) with a partially different pharmacological profile. The first generation aromatase inhibitor, aminoglutethimide, has been replaced by more potent and less toxic inhibitors belonging to the triazole class (anastrozole and letrozole) and, more recently, the steroidal aromatase inactivator exemestane [1-3]. These drugs have all revealed a better toxicity profile and, in general, an improved antitumour activity, compared with conventional therapy. Faslodex, the first representative of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in patients resistant to tamoxifen [4].

Aminoglutethimide↗
PubMed2006

RETIRED: Mastalgia.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Breast Diseases↗
PubMed2001

Matrix metalloproteinase-2 (MMP-2) is associated with the risk for a relapse in postmenopausal patients with node-positive breast carcinoma treated with antiestrogen adjuvant therapy.

Node-positive breast carcinoma is an aggressive disease. Postmenopausal patients benefit from antiestrogen adjuvant therapy. Predictive markers could, however, be useful in selecting these patients for different modalities of adjuvant therapy. Recently, we showed that MMP-2 (72 kD type IV collagenase/gelatinase A) is correlated with unfavorable prognosis in premenopausal breast carcinoma patients. Expression of the immunoreactive protein for MMP-2 was evaluated prospectively in this study in paraffin tissue sections from primary tumors of 100 postmenopausal, node-positive breast carcinoma patients treated with an adjuvant antiestrogen therapy. A specific MMP-2 monoclonal antibody in an avidin-biotin immunohistochemical staining was used. Sixty nine percent of the samples were MMP-2 positive. Eighty three percent of the MMP-2 negative patients lived for 5 years without a recurrence, while only 67% of the patients with an MMP-2 positive primary tumor were recurrence-free at that time (p < 0.05; log rank analysis). MMP-2 positivity showed a significant correlation with shortened survival in patients with a small primary tumor (T1-2) and a low axillary tumor burden. One hundred percent of these patients with an MMP-2 negative breast carcinoma survived for 5 years, compared to 73% of the MMP-2 positive cases alive at that time (p = 0.02). In conclusion, we show here that MMP-2 is a prognostic indicator in postmenopausal patients with node-positive breast carcinoma with a low tumor burden, and that it predicts a risk for failure in antiestrogen adjuvant therapy. It might have predictive value in selecting the most efficient adjuvant therapy in this set of patients.

Aged↗
PubMed1990

Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts.

The clinical use of anti-oestrogens in breast cancer therapy has traditionally been restricted to tumours that contain measurable oestrogen receptor protein. However, it is now widely recognised that the clinical response to adjuvant anti-oestrogen therapy appears to be independent of the oestrogen receptor content of the primary tumour. The study reported here was designed to investigate the possibility that human stromal cells can respond to anti-oestrogens by an increased synthesis of the inhibitory growth factor, transforming growth factor beta (TGF-beta). Two established human fetal fibroblast strains were used as models for the breast cancer stromal fibroblasts. These cells were found to respond to the addition of anti-oestrogens by a large increase in their synthesis of biologically active TGF-beta. Despite the application of ligand binding, immunoassay and Northern analysis, no oestrogen receptor or oestrogen receptor mRNA was detected in either of the human fetal fibroblasts strains. These observations may provide a mechanism of action of anti-oestrogens that is independent of the presence of oestrogen receptor in the tumour epithelial cells, and thus provide an explantation for the counter-intuitive results of adjuvant anti-oestrogen action.

Blotting, Northern↗