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Asian Journal of Andrology Sep 2012Therapy based on androgenic deprivation is one of the standard treatments that many prostate cancer patients receive. Moreover, its use is increasing owing to a clear... (Review)
Review
Therapy based on androgenic deprivation is one of the standard treatments that many prostate cancer patients receive. Moreover, its use is increasing owing to a clear expansion of the indications for this therapy in patients with localized prostate cancer. Despite classically being considered to be well tolerated, androgenic deprivation has adverse effects. Of these, the loss of mineral bone mass is particularly notable and can lead to osteoporosis, as well as an increased risk of bone fracture. Some fractures, such as hip fractures, may have serious consequences. Useful procedures such as bone densitometry can aid in the diagnosis of these conditions. Once diagnosed, decreases in mineral bone mass can be managed by dietary recommendations, general changes in lifestyle or medication. We review the most important randomized controlled trials evaluating different drugs (bisphosphonates, denosumab and toremifene) in the prevention of bone loss and in the reduction in fracture risk in prostate cancer patients treated with androgen-deprivation therapy. Following the applicable recommendations, urologists must carefully monitor the bone health of prostate cancer patients subjected to androgenic deprivation to obtain an early diagnosis and apply the appropriate general and/or therapeutic measures if necessary.
Topics: Androgen Antagonists; Bone Density; Bone Neoplasms; Diphosphonates; Humans; Male; Prostatic Neoplasms
PubMed: 22902912
DOI: 10.1038/aja.2012.70 -
Cancer Chemotherapy and Pharmacology Feb 2018A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum... (Comparative Study)
Comparative Study Randomized Controlled Trial
Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study.
A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.
Topics: Aged; Alkaline Phosphatase; Antineoplastic Agents, Hormonal; Bone and Bones; Breast Neoplasms; Chemotherapy, Adjuvant; Cholesterol; Cholesterol, LDL; Collagen Type I; Female; Humans; Letrozole; Lipids; Middle Aged; Postmenopause; Prospective Studies; Toremifene
PubMed: 29196963
DOI: 10.1007/s00280-017-3491-6 -
International Journal of Women's Health Sep 2013Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration... (Review)
Review
Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique. This review first discusses the rationale for developing ospemifene, including its mechanism of action, and then focuses on the clinical development of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Included are discussions of the effects of ospemifene on the endometrium, serum lipids, coagulation markers, bone, and breast cancer. In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Ospemifene warrants further clinical investigation for the treatment and prevention of osteoporosis and breast cancer.
PubMed: 24109197
DOI: 10.2147/IJWH.S39146 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects....
Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs-especially toremifene-substantially increased diabetes risk in breast cancer patients (OR 1.63, = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, < 0.001) and death (OR 0.13, < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes.
PubMed: 34577625
DOI: 10.3390/ph14090925 -
Antiviral Research Jan 2017Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human...
Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann-Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.
Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Clarithromycin; Drug Combinations; Drug Synergism; Ebolavirus; Hemorrhagic Fever, Ebola; High-Throughput Screening Assays; Humans; Mefloquine; Sphingomyelin Phosphodiesterase; Toremifene; Triazoles; Vero Cells; Virus Internalization
PubMed: 27890675
DOI: 10.1016/j.antiviral.2016.11.017 -
Acta Medica Okayama Aug 2009Toremifene citrate is expected to prevent drug resistance in cancer patients by inhibiting p-glycoprotein activity. The safety and efficacy of combination therapy with...
Toremifene citrate is expected to prevent drug resistance in cancer patients by inhibiting p-glycoprotein activity. The safety and efficacy of combination therapy with high-dose toremifene citrate and paclitaxel were investigated. Between December 2003 and June 2004, 15 women with a mean age of 53 years old with metastatic breast cancer were enrolled. The administration schedule was 80 mg/m2 of paclitaxel given on Days 1, 8, and 15, and 120 mg/day of toremifene citrate orally administered starting on Day 18. On Days 32 and 39, paclitaxel was concurrently administered again. Toxicities, response rate, and time to treatment failure were assessed. All patients had been treated with endocrine or chemotherapy. Grade 3 leukopenia occurred in 2 patients on the administration of paclitaxel alone, and grade 3 febrile neutropenia occurred in 1 patient given the combination therapy. There was no grade 3 or greater non-hematological toxicity. There was no complete response and 1 partial response, producing a response rate of 6.7%. Median time to treatment failure was 2.7 months. Combination therapy of paclitaxel and toremifene was safe and well tolerated with minimal toxicity. Further clinical trials targeting patients with functional p-glycoprotein are warranted.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Paclitaxel; Toremifene
PubMed: 19727203
DOI: 10.18926/AMO/31816 -
Cancer May 2010Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized that toremifene as compared with tamoxifen given as adjuvant therapy for early stage breast cancer would result in equivalent survival with an improved side effect profile, therefore, providing superior therapeutic efficacy.
METHODS
The North American Fareston versus Tamoxifen Adjuvant trial assigned 1813 perimenopausal or postmenopausal women with hormone receptor (HR)-positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS) and overall survival (OS).
RESULTS
Median follow-up was 59 months. The baseline characteristics of the 2 treatment groups were well-balanced. On the basis of intent-to-treat, 5-year actuarial DFS was not significantly different between tamoxifen and toremifene (91.2% [standard error of the mean [SE] 1.2%] vs 91.2% [SE 1.1%], respectively). Similarly, 5-year actuarial OS was not significantly different between tamoxifen and toremifene (92.7% [SE 1.1%] vs 93.7% [SE 1.0%], respectively). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene versus tamoxifen in terms of OS (OR = 0.951; 95% confidence interval [CI], 0.623-1.451, P = .951) or DFS (OR = 1.037; 95% CI, 0.721-1.491, P = .846). Adverse events were similar in the 2 groups.
CONCLUSIONS
Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of HR-positive patients with either tamoxifen or toremifene is appropriate.
Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene
PubMed: 20209619
DOI: 10.1002/cncr.24940 -
Biochemical Pharmacology Nov 2017Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an... (Review)
Review
Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquired resistance is often observed, constituting a major challenge for extending patient life expectancy. The mechanisms responsible for these treatment failures remain unclear, indicating the requirement for other targets and better predictors for patient response to Tam. One of Tam's off-targets of interest is the microsomal antiestrogen binding site (AEBS), a multiproteic complex made up of the cholesterol-5,6-epoxide hydrolase (ChEH) enzymes that are involved in the late stages of cholesterol biosynthesis. Tam and other selective ER modulators stimulate oxidative stress and inhibit the ChEH subunits at pharmacological doses, triggering the production and accumulation of cholesterol-5,6-epoxide metabolites responsible for BC cell differentiation and death. However, inhibition of the cholesterogenic activity of the AEBS subunits also induces the accumulation of sterol precursors, which triggers a survival autophagy to impair Tam's efficacy. Altogether, these studies have highlighted the involvement of cholesterol metabolism in the pharmacology of Tam that has provided new clues on how to improve its therapeutic efficacy in both BC and other cancers as well as offering a new rationale for developing more efficient drugs for BC treatment.
Topics: Animals; Autophagy; Breast Neoplasms; Cell Death; Cell Differentiation; Cholesterol; Estrogen Antagonists; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen; Treatment Outcome
PubMed: 28642035
DOI: 10.1016/j.bcp.2017.06.120 -
Endocrine-related Cancer Aug 2011The majority (∼70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα)... (Review)
Review
The majority (∼70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+ breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled 'Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer', Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors.
Topics: Aromatase Inhibitors; Breast Neoplasms; Cell Cycle; Female; Humans; Neoplasms, Hormone-Dependent; Retinoblastoma Protein; Second Messenger Systems
PubMed: 21613412
DOI: 10.1530/ERC-11-0112 -
The Journal of Steroid Biochemistry and... Jan 2008Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human...
Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.8+/-1.3 microM, 1+/-0.3 microM and 60.4+/-17.2 microM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000 microg/day), atamestane (1000 microg/day), tamoxifen (100 microg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.
Topics: Androstenedione; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Mice; Mice, SCID; Prognosis; Toremifene; Transfection; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 17942301
DOI: 10.1016/j.jsbmb.2007.04.005