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Journal of the Advanced Practitioner in... Mar 2017DE, a 31-year-old premenopausal woman with a nonsignificant medical history, noticed a right breast mass after playing basketball in September 2011. She initially... (Review)
Review
DE, a 31-year-old premenopausal woman with a nonsignificant medical history, noticed a right breast mass after playing basketball in September 2011. She initially attributed the mass to slight trauma, but after 2 weeks, she realized the mass was increasing in size. Her primary care physician ordered a bilateral screening mammogram and ultrasound. Mammography revealed no evidence of malignancy in the left breast. In the right breast, at the 7 o'clock position, a loose cluster of faint calcifications spanned a 2.2-cm area. Ultrasound confirmed an irregular hypoechoic mass in the right breast measuring 3.5 × 2.7 × 2.8 cm. Ultrasound of the right axilla identified two enlarged right axillary lymph nodes. Ultrasound core-needle biopsy of the suspicious right breast mass confirmed invasive ductal carcinoma, nuclear grade 2, Ki67 index of 55%, estrogen receptor-positive (H score of 180), progesterone receptor-positive (H score of 135), HER2-positive (3+ on immunohistochemistry). Utilizing the TNM (tumor, node, metastasis) staging system, she was clinically staged with a stage IIB (cT2, cN1, M0) invasive breast tumor. The computerized axial tomography (CT) scan of the chest, abdomen, and pelvis demonstrated the known right breast mass and two enlarged right axillary lymph nodes; however, no metastatic disease was noted. Nuclear bone scan revealed no bone metastases. Her medical oncologist recommended she receive neoadjuvant chemotherapy. The patient was treated with 6 cycles of neoadjuvant docetaxel at 75 mg/m², carboplatin at an AUC (area under the curve) of 6, and trastuzumab (Herceptin) at 6 mg/kg (TCH), which she tolerated well. She then underwent a right segmental mastectomy with axillary lymph node dissection and was found to have a residual 1.0-cm invasive ductal carcinoma, representing a 60% tumor volume reduction. None of 13 axillary lymph nodes were positive for disease. Pathologic staging confirmed a stage IA (ypT1, ypN0, M0) tumor. DE completed 33 fractions of radiation therapy to the right breast. She initiated endocrine therapy with tamoxifen at 20 mg daily and received 1 year of maintenance trastuzumab (6 mg/kg). Due to vaginal discharge and weight gain, endocrine therapy was switched from tamoxifen to toremifene (Fareston), which she tolerated relatively well. She continued routine follow-up, with no evidence of disease. In September 2014, DE presented to her primary care physician complaining of left hip pain. Magnetic resonance imaging (MRI) of the left hip revealed T2 hyperintense masses within the right anterior superior iliac crest, right sacrum, and left iliac body consistent with skeletal metastases. She was referred back to her medical oncologist, and per National Comprehensive Cancer Network (NCCN) guidelines, a biopsy of the suspicious lesion was obtained. The bone biopsy of the lytic lesion was consistent with metastatic breast cancer, which was estrogen receptor-positive, progesterone receptor-positive, and HER2-positive (3+ on immunohistochemistry). Restaging CT scan of the chest, abdomen, and pelvis revealed new 4- to 6-mm pulmonary nodules, hilar and mediastinal lymphadenopathy, new liver lesions, and bone lesions. Nuclear bone scan confirmed multiple bone metastases of the right and left iliac bones and sternum. Complete blood cell count with differential and complete metabolic panel were within normal ranges. The CA 27-29 tumor marker for breast cancer was elevated at 495 U/mL (normal range, < 37 U/mL). DE was understandably devastated by the new diagnosis. She questioned how the treatment plan was to be established. Her medical oncologist struck a somewhat optimistic tone. He explained that metastatic breast cancer was not yet considered to be curable, but periods of disease stability and chronicity were possible. He explained that the HER2 positivity was perhaps the most important factor in delineating her treatment options. He told her that current treatment options were numerous and increasing in number.
PubMed: 29900024
DOI: No ID Found -
The Urologic Clinics of North America Nov 2012In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points... (Review)
Review
In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.
Topics: Androgen Antagonists; Antibodies, Monoclonal, Humanized; Bone Density; Bone Neoplasms; Clinical Trials as Topic; Clodronic Acid; Denosumab; Diphosphonates; Fractures, Spontaneous; Humans; Imidazoles; Male; Osteoclasts; Osteoporosis; Pamidronate; Prostatic Neoplasms; Quality of Life; Samarium; Toremifene; Zoledronic Acid
PubMed: 23084529
DOI: 10.1016/j.ucl.2012.07.009 -
Journal of Proteome Research Nov 2020The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the death of more than...
The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the death of more than 675,000 worldwide and over 150,000 in the United States alone. However, there are currently no approved effective pharmacotherapies for COVID-19. Here, we combine homology modeling, molecular docking, molecular dynamics simulation, and binding affinity calculations to determine potential targets for toremifene, a selective estrogen receptor modulator which we have previously identified as a SARS-CoV-2 inhibitor. Our results indicate the possibility of inhibition of the spike glycoprotein by toremifene, responsible for aiding in fusion of the viral membrane with the cell membrane, via a perturbation to the fusion core. An interaction between the dimethylamine end of toremifene and residues Q954 and N955 in heptad repeat 1 (HR1) perturbs the structure, causing a shift from what is normally a long, helical region to short helices connected by unstructured regions. Additionally, we found a strong interaction between toremifene and the methyltransferase nonstructural protein (NSP) 14, which could be inhibitory to viral replication via its active site. These results suggest potential structural mechanisms for toremifene by blocking the spike protein and NSP14 of SARS-CoV-2, offering a drug candidate for COVID-19.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Repositioning; Exoribonucleases; Humans; Molecular Docking Simulation; Pandemics; Pneumonia, Viral; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Toremifene; Viral Nonstructural Proteins
PubMed: 32907334
DOI: 10.1021/acs.jproteome.0c00397 -
Infectious Diseases of Poverty 2015There is currently no effective treatment for the Ebola virus (EBOV) thus far. Most drugs and vaccines developed to date have not yet been approved for human trials. Two...
There is currently no effective treatment for the Ebola virus (EBOV) thus far. Most drugs and vaccines developed to date have not yet been approved for human trials. Two FDA-approved c-AbI1 tyrosine kinase inhibitors Gleevec and Tasigna block the release of viral particles; however, their clinical dosages are much lower than the dosages required for effective EBOV suppression. An α-1,2-glucosidase inhibitor Miglustat has been shown to inhibit EBOV particle assembly and secretion. Additionally, the estrogen receptor modulators Clomiphene and Toremifene prevent membrane fusion of EBOV and 50-90% of treated mice survived after Clomiphene/Toremifene treatments. However, the uptake efficiency of Clomiphene by oral administration is very low. Thus, I propose a hypothetical treatment protocol to treat Ebola virus infection with a cumulative use of both Miglustat and Toremifene to inhibit the virus effectively and synergistically. EBOV infection induces massive apoptosis of peripheral lymphocytes. Also, cytolysis of endothelial cells triggers disseminated intravascular coagulation (DIC) and subsequent multiple organ failures. Therefore, blood transfusions and active treatments with FDA-approved drugs to treat DIC are also recommended.
PubMed: 25984303
DOI: 10.1186/s40249-015-0055-z -
Annals of Oncology : Official Journal... Dec 2004Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years.
PATIENTS AND METHODS
1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy.
RESULTS
Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three).
CONCLUSIONS
Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer.
Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Quality of Life; Receptors, Estrogen; Tamoxifen; Toremifene; Treatment Outcome
PubMed: 15550579
DOI: 10.1093/annonc/mdh463 -
Current Opinion in Endocrinology,... Jun 2007The aim of this review is to summarize new concepts and concerns regarding treatment-related osteoporosis, diabetes, and cardiovascular disease in men receiving androgen... (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to summarize new concepts and concerns regarding treatment-related osteoporosis, diabetes, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer.
RECENT FINDINGS
Gonadotropin-releasing hormone agonists increase bone turnover, decrease bone mineral density, and increase fracture risk. Bisphosphonates, selective and estrogen receptor modulators significantly increase bone mineral density during androgen deprivation therapy. Ongoing randomized controlled trials will assess efficacy of denosumab, toremifene, and zoledronic acid to prevent fractures in this setting. Gonadotropin-releasing hormone agonists also increase fat mass, decrease insulin sensitivity, and increase serum lipoproteins. In contrast to the classical metabolic syndrome, however, the phenotype of men during androgen deprivation therapy is characterized by increased high-density lipoprotein cholesterol and preferential accumulation of subcutaneous fat. Gonadotropin-releasing hormone agonists are associated with greater risk of incident diabetes and cardiovascular disease in men with prostate cancer.
SUMMARY
Androgen therapy increases risk of fractures, diabetes mellitus, and cardiovascular disease in men with prostate cancer. Current and planned studies will evaluate strategies to prevent these treatment-related adverse effects.
Topics: Androgen Antagonists; Androgens; Cardiovascular Diseases; Diabetes Mellitus; Endocrinology; Fractures, Bone; Gonadotropin-Releasing Hormone; Humans; Male; Osteoporosis; Prostatic Neoplasms; Risk Factors
PubMed: 17940447
DOI: 10.1097/MED.0b013e32814db88c -
BMC Cancer May 2012In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a... (Comparative Study)
Comparative Study
A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study.
BACKGROUND
In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen.
METHODS
Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups.
RESULTS
Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer.
CONCLUSION
Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.
Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Protocols; Breast Neoplasms; Cohort Studies; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Premenopause; Receptors, Estrogen; Receptors, Progesterone; Reproducibility of Results; Retrospective Studies; Tamoxifen; Toremifene
PubMed: 22548922
DOI: 10.1186/1471-2407-12-161 -
Frontiers in Microbiology 2021Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the... (Review)
Review
Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the efficiency of screening of antimicrobial compounds against a broad spectrum of pathogens, deep learning has also the potential to efficiently and reliably identify drug candidates against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consequently, deep learning has been successfully used for the identification of a number of potential drugs against SARS-CoV-2, including Atazanavir, Remdesivir, Kaletra, Enalaprilat, Venetoclax, Posaconazole, Daclatasvir, Ombitasvir, Toremifene, Niclosamide, Dexamethasone, Indomethacin, Pralatrexate, Azithromycin, Palmatine, and Sauchinone. This mini-review discusses recent advances and future perspectives of deep learning-based SARS-CoV-2 drug discovery.
PubMed: 34777286
DOI: 10.3389/fmicb.2021.739684 -
Acta Pharmacologica Sinica Aug 2021To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry...
To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.
Topics: Antiviral Agents; Cell Line; Drug Approval; Drug Repositioning; High-Throughput Screening Assays; Humans; Microbial Sensitivity Tests; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33116249
DOI: 10.1038/s41401-020-00556-6 -
Journal of Virology Apr 2019Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple... (Comparative Study)
Comparative Study
Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV. Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases.
Topics: Animals; Antiviral Agents; COS Cells; Chlorocebus aethiops; Cricetinae; Drug Evaluation, Preclinical; Ebolavirus; HEK293 Cells; Hemorrhagic Fever, Ebola; Humans; Indoles; Lassa Fever; Lassa virus; Vero Cells; Virus Internalization
PubMed: 30700611
DOI: 10.1128/JVI.02185-18