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International Journal of Cancer Mar 2013We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the...
We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.
Topics: Adult; Cytochrome P-450 CYP2D6; Humans; Male; Oxidation-Reduction; Selective Estrogen Receptor Modulators; Structure-Activity Relationship; Tamoxifen; Toremifene
PubMed: 22915089
DOI: 10.1002/ijc.27794 -
Patient Related Outcome Measures 2014Androgen deprivation therapy (ADT) constitutes the first-line treatment for patients with locally advanced tumors, recurrent or metastatic disease. Given its widespread... (Review)
Review
Androgen deprivation therapy (ADT) constitutes the first-line treatment for patients with locally advanced tumors, recurrent or metastatic disease. Given its widespread use, clinicians should be familiar with common side effects of this treatment. This review focuses on common side effects of ADT and available treatment options to control the side effects. Also, it briefly compares continuous ADT with other therapeutic approaches for androgen deprivation in prostate cancer patients. Similar to hormonal medications, newer non-hormonal therapeutic options including gabapentin and acupuncture have at best moderate effect in controlling hot flashes in patients on ADT. Supervised and/or home exercise programs significantly improve ADT-related fatigue, metabolic/cardiovascular side effects, and cognitive dysfunction. Denosumab, a human monoclonal antibody against RANK-L, is more effective than bisphosphonates in preventing skeletal-related events in patients with metastatic or castrate-resistant prostate cancer and unlike bisphosphonates, it can also reduce the risk of vertebral fractures in men receiving ADT for non-metastatic prostate cancer. Toremifene, a selective estrogen receptor inhibitor, has dual beneficial effects on ADT-related osteoporosis and metabolic dysfunction. Metformin coupled with lifestyle modification is also a well-tolerated treatment for metabolic changes during ADT. While producing similar oncological outcomes, intermittent ADT is associated with higher quality of life in patients under ADT by improving bone health, less metabolic and hematologic complications, and fewer hot flashes and sexual dysfunction events.
PubMed: 25045284
DOI: 10.2147/PROM.S52788 -
Archives of Pathology & Laboratory... Sep 2023Whether androgen receptor (AR) expression can predict prognosis in breast cancer is under debate.
CONTEXT.—
Whether androgen receptor (AR) expression can predict prognosis in breast cancer is under debate.
OBJECTIVE.—
To analyze, retrospectively, the prognostic and treatment-predictive ability of AR status in breast cancer.
DESIGN.—
A total of 5765 patients diagnosed with primary invasive breast cancer without distant metastasis in the adjuvant setting were analyzed. The propensity score-matching method was used to develop a new cohort of 3978 patients (1989 patients each) in which important prognostic factors were balanced.
RESULTS.—
Positive AR expression is an independent prognostic factor for disease-free survival and overall survival. Estrogen receptor (ER)+ and progesterone receptor (PR)+ AR+ breast cancer patients had the longest survival, whereas ER-PR-AR- breast cancer patients had the shortest survival. The ER/PR/AR combinations could not predict the treatment effects for adjuvant trastuzumab but could be used for adjuvant chemotherapy and endocrine therapy selection. The worst survival was found in ER+PR-AR- patients receiving toremifene, ER+PR-AR+ patients receiving exemestane, ER+PR+AR- patients receiving anthracycline, and ER-PR-AR+ patients receiving taxanes. ER+PR-AR-, ER-PR-AR+, and ER-PR-AR- patients were associated with the worst survival among those who received radiotherapy and anthracycline plus taxanes.
CONCLUSIONS.—
AR in combination with ER and PR could predict the prognosis and treatment effects of chemotherapy, endocrine therapy, and radiotherapy in the adjuvant setting.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Receptors, Androgen; Retrospective Studies; Receptors, Estrogen; Anthracyclines; Taxoids; Receptors, Progesterone
PubMed: 36508355
DOI: 10.5858/arpa.2021-0590-OA -
Clinical Interventions in Aging 2014During the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and vulvar and vaginal atrophy... (Review)
Review
During the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and vulvar and vaginal atrophy (VVA). Unlike vasomotor symptoms, vaginal dryness and dyspareunia, the main symptoms of VVA, typically worsen without treatment and can significantly impact the quality of life. Up to 60% of postmenopausal women may be affected by VVA, but many women unfortunately do not seek treatment due to embarrassment or other factors. After 20+ years in development, ospemifene (Osphena™) was approved by the US Food and Drug Administration in 2013 for treatment of moderate-to-severe dyspareunia associated with VVA due to menopause. As the first non-hormonal alternative to estrogen-based products for this indication, the approval of ospemifene represents a significant milestone in postmenopausal women's health. Ospemifene is a non-steroidal estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), from the same chemical class as the breast cancer drugs tamoxifen and toremifene. Unlike other selective estrogen receptor modulators, ospemifene exerts a strong, nearly full estrogen agonist effect in the vaginal epithelium, making it well suited for the treatment of dyspareunia in postmenopausal women. Results of Phase III clinical trials showed that ospemifene significantly improved the vaginal maturation index (decreased parabasal cells and increased superficial cells), decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) compared to placebo. Long-term safety studies revealed that 60 mg ospemifene given daily for 52 weeks was well tolerated and was not associated with any endometrium or breast-related safety concerns. This review discusses the preclinical and clinical data supporting the use of ospemifene for the treatment of dyspareunia associated with VVA due to menopause and provides an overview of its clinical safety.
Topics: Animals; Atrophy; Dyspareunia; Female; Humans; Postmenopause; Randomized Controlled Trials as Topic; Rats; Selective Estrogen Receptor Modulators; Tamoxifen; Vagina; Vulva
PubMed: 25419123
DOI: 10.2147/CIA.S73753 -
Cleveland Clinic Journal of Medicine Jun 2020To date, there are no effective antiviral medications for COVID-19. Drug repurposing, a strategy that uses existing drugs, offers potential prevention and treatment...
To date, there are no effective antiviral medications for COVID-19. Drug repurposing, a strategy that uses existing drugs, offers potential prevention and treatment options for COVID-19. We discuss one treatment strategy that combines anti-inflammatory (melatonin) and antiviral (toremifene) agents for patients infected with SARS-CoV-2 from network medicine-based findings. We also describe the pathobiology and immunologic characteristics of COVID-19 and highlight the rationale of combination drug treatment to rescue the pulmonary and cardiovascular conditions resulting from COVID-19. A preliminary analysis reveals a high potential for the synergistic effects of melatonin and toremifene to reduce viral infection and replication, and the aberrant host inflammatory responses, offering strong biologic plausibility as an effective therapy for COVID-19.
PubMed: 32606050
DOI: 10.3949/ccjm.87a.ccc037 -
Antimicrobial Agents and Chemotherapy Mar 2017The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated a search for new antibacterial agents against...
The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated a search for new antibacterial agents against oral bacterial pathogens. As a result of failing traditional approaches, drug repurposing has emerged as a novel paradigm to find new antibacterial agents. In this study, we examined the effects of the FDA-approved anticancer agent toremifene against the oral bacteria and We found that the drug was able to inhibit the growth of both pathogens, as well as prevent biofilm formation, at concentrations ranging from 12.5 to 25 μM. Moreover, toremifene was shown to eradicate preformed biofilms at concentrations ranging from 25 to 50 μM. In addition, we found that toremifene prevents and biofilm formation on titanium surfaces. A time-kill study indicated that toremifene is bactericidal against Macromolecular synthesis assays revealed that treatment with toremifene does not cause preferential inhibition of DNA, RNA, or protein synthesis pathways, indicating membrane-damaging activity. Biophysical studies using fluorescent probes and fluorescence microscopy further confirmed the membrane-damaging mode of action. Taken together, our results suggest that the anticancer agent toremifene is a suitable candidate for further investigation for the development of new treatment strategies for oral bacterial infections.
Topics: Anti-Bacterial Agents; Antineoplastic Agents, Hormonal; Biofilms; Cell Membrane; Cell Membrane Permeability; Dental Plaque; Drug Repositioning; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Periodontitis; Porphyromonas gingivalis; Streptococcus mutans; Titanium; Toremifene
PubMed: 27993858
DOI: 10.1128/AAC.01846-16 -
Breast Cancer Research and Treatment Nov 2003Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus-pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus-pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.
Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Antithrombin III; Aspartate Aminotransferases; Breast Neoplasms; Central Nervous System Diseases; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hypercalcemia; Luteinizing Hormone; Middle Aged; Pentoxifylline; Postmenopause; Sex Hormone-Binding Globulin; Tamoxifen; Treatment Outcome; Vagina
PubMed: 14692654
DOI: 10.1023/B:BREA.0000003957.54851.11 -
PLoS Pathogens Feb 2021Many small molecules have been identified as entry inhibitors of filoviruses. However, a lack of understanding of the mechanism of action for these molecules limits...
Many small molecules have been identified as entry inhibitors of filoviruses. However, a lack of understanding of the mechanism of action for these molecules limits further their development as anti-filoviral agents. Here we provide evidence that toremifene and other small molecule entry inhibitors have at least three distinctive mechanisms of action and lay the groundwork for future development of anti-filoviral agents. The three mechanisms identified here include: (1) direct binding to the internal fusion loop region of Ebola virus glycoprotein (GP); (2) the HR2 domain is likely the main binding site for Marburg virus GP inhibitors and a secondary binding site for some EBOV GP inhibitors; (3) lysosome trapping of GP inhibitors increases drug exposure in the lysosome and further improves the viral inhibition. Importantly, small molecules targeting different domains on GP are synergistic in inhibiting EBOV entry suggesting these two mechanisms of action are distinct. Our findings provide important mechanistic insights into filovirus entry and rational drug design for future antiviral development.
Topics: A549 Cells; Animals; Antiviral Agents; Chlorocebus aethiops; Ebolavirus; Glycoproteins; Hemorrhagic Fever, Ebola; Host-Pathogen Interactions; Humans; Lysosomes; Small Molecule Libraries; Vero Cells; Viral Envelope Proteins; Virus Internalization
PubMed: 33539432
DOI: 10.1371/journal.ppat.1009312 -
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