Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer
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Prospective Study on Gynaecological Effects of Two Antioestrogens Tamoxifen and Toremifene in Postmenopausal Women
British Journal of Cancer (2001) 84(7), 897–902 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1703, available online at http://www.idealibrary.com on http://www.bjcancer.com Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women MB Marttunen1, B Cacciatore1, P Hietanen2, S Pyrhönen2, A Tiitinen1, T Wahlström3 and O Ylikorkala1 1Departments of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HYKS, Finland; 2Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029 HYKS, Finland; 3Department of Pathology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HYKS, Finland Summary To assess and compare the gynaecological consequences of the use of 2 antioestrogens we examined 167 postmenopausal breast cancer patients before and during the use of either tamoxifen (20 mg/day, n = 84) or toremifene (40 mg/day, n = 83) as an adjuvant treatment of stage II–III breast cancer. Detailed interview concerning menopausal symptoms, pelvic examination including transvaginal sonography (TVS) and collection of endometrial sample were performed at baseline and at 6, 12, 24 and 36 months of treatment. In a subgroup of 30 women (15 using tamoxifen and 15 toremifene) pulsatility index (PI) in an uterine artery was measured before and at 6 and 12 months of treatment. The mean (±SD) follow-up time was 2.3 ± 0.8 years. 35% of the patients complained of vasomotor symptoms before the start of the trial. This rate increased to 60.0% during the first year of the trial, being similar among patients using tamoxifen (57.1%) and toremifene (62.7%). -
Tamoxifen, Raloxifene Upheld for Prevention
38 WOMEN’S HEALTH MAY 1, 2010 • FAMILY PRACTICE NEWS Tamoxifen, Raloxifene Upheld for Prevention BY KERRI WACHTER 9,736 on tamoxifen and 9,754 on ralox- 1.24, which was significant (P = .01). Both events) did not appear to be as effective ifene. The differences in numbers are due drugs reduced the risk of invasive breast as tamoxifen (57 events) in preventing WASHINGTON — Tamoxifen and to a combination of loss during follow- cancer by roughly 50% in the original re- noninvasive breast cancer (P = .052). raloxifene offer women at high risk of up or follow-up data becoming available port (median follow-up 47 months). “Now with additional follow-up, those developing breast cancer two effective for women who were lost to follow-up “We have estimated, however, that differences have narrowed,” he said. At options to prevent the disease, based on in the original report. Women on ta- this difference in the raloxifene-treated 8 years, there was no statistical signifi- 8 years of follow-up data for more than moxifen received 20 mg/day and those group represents 76% of tamoxifen’s cance between the two groups with a 19,000 women in the STAR trial. on raloxifene received 60 mg/day. chemopreventative benefit, which trans- risk ratio of 1.22 (P = .12). The relative While tamoxifen proved significantly At an average follow-up of 8 years, the lates into at 38% reduction in invasive risk of 1.22 favors tamoxifen, but ralox- more effective in preventing invasive breast relative risk of invasive breast cancer on breast cancers,” Dr. -
Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin
Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/01/17/dmd.117.078428.DC1 1521-009X/46/4/367–379$35.00 https://doi.org/10.1124/dmd.117.078428 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:367–379, April 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans s Timothy Wong, Zhican Wang, Brian D. Chapron, Mizuki Suzuki, Katrina G. Claw, Chunying Gao, Robert S. Foti, Bhagwat Prasad, Alenka Chapron, Justina Calamia, Amarjit Chaudhry, Erin G. Schuetz, Ronald L. Horst, Qingcheng Mao, Ian H. de Boer, Timothy A. Thornton, and Kenneth E. Thummel Departments of Pharmaceutics (T.W., Z.W., B.D.C., M.S., K.G.C., C.G., B.P., Al.C., J.C., Q.M., K.E.T.), Medicine and Kidney Research Institute (I.H.d.B.), and Biostatistics (T.A.T.), University of Washington, Seattle, Washington; Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California (Z.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, Massachusetts (R.S.F.); St. Jude Children’s Research Hospital, Memphis, Tennessee Downloaded from (Am.C., E.G.S.); and Heartland Assays LLC, Ames, Iowa (R.L.H.) Received September 1, 2017; accepted January 10, 2018 ABSTRACT dmd.aspetjournals.org Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in with the rates of dehydroepiandrosterone sulfonation. Further analysis regulating the biologic effects of vitamin D in the body. -
Transcriptomic Characterization of Fibrolamellar Hepatocellular
Transcriptomic characterization of fibrolamellar PNAS PLUS hepatocellular carcinoma Elana P. Simona, Catherine A. Freijeb, Benjamin A. Farbera,c, Gadi Lalazara, David G. Darcya,c, Joshua N. Honeymana,c, Rachel Chiaroni-Clarkea, Brian D. Dilld, Henrik Molinad, Umesh K. Bhanote, Michael P. La Quagliac, Brad R. Rosenbergb,f, and Sanford M. Simona,1 aLaboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065; bPresidential Fellows Laboratory, The Rockefeller University, New York, NY 10065; cDivision of Pediatric Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; dProteomics Resource Center, The Rockefeller University, New York, NY 10065; ePathology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and fJohn C. Whitehead Presidential Fellows Program, The Rockefeller University, New York, NY 10065 Edited by Susan S. Taylor, University of California, San Diego, La Jolla, CA, and approved September 22, 2015 (received for review December 29, 2014) Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a exon of DNAJB1 and all but the first exon of PRKACA. This deletion of ∼400 kb in chromosome 19, resulting in a fusion of the produced a chimeric RNA transcript and a translated chimeric genes for the heat shock protein, DNAJ (Hsp40) homolog, subfam- protein that retains the full catalytic activity of wild-type PKA. ily B, member 1, DNAJB1, and the catalytic subunit of protein ki- This chimeric protein was found in 15 of 15 FLHCC patients nase A, PRKACA. The resulting chimeric transcript produces a (21) in the absence of any other recurrent mutations in the DNA fusion protein that retains kinase activity. -
Effects of Biologically Active Metabolites of Tamoxifen on the Proliferation Kinetics of MCF-7 Human Breast Cancer Cells in Vitro
[CANCER RESEARCH 43, 4618-4624, October 1983] Effects of Biologically Active Metabolites of Tamoxifen on the Proliferation Kinetics of MCF-7 Human Breast Cancer Cells in Vitro Roger R. Reddel, Leigh C. Murphy, and Robert L. Sutherland1 Ludwig Institute for Cancer Research (Sydney Branch), University of Sydney, Sydney, New South Wales 2006, Australia ABSTRACT tumor tissues of patients treated with tamoxifen is DMT, with 4OHT being present at much lower concentrations (1, 7,13, 25). The effects of two major metabolites of tamoxifen, /V-de- Prompted no doubt in part by the early misidentification of the methyltamoxifen (DMT) and 4-hydroxytamoxifen (4OHT), on major metabolite as 4OHT, there has been considerable interest MCF-7 œil proliferation and cell cycle kinetic parameters were in the antiestrogenic and antitumor activity of 4OHT (2, 3, 6,15, compared with those of the parent compound. All three com 16, 33). In contrast, there have been very few studies on the pounds produced dose-dependent decreases in the rate of cell biological activity of DMT (6, 33). proliferation which were accompanied by decreases in the per In the present study, we have attempted to answer the follow centage of S- and G2-M-phase cells. 4OHT was 100- to 167-fold ing questions. Do the metabolites DMT and 40HT differ from more potent than both tamoxifen and DMT in producing these tamoxifen in their actions on the proliferation and cell cycle effects, and this was correlated with their relative binding affini kinetics of human breast cancer cells? What are the relative ties (RBAs) for the cytoplasmic estrogen receptor (ER) (17/3- potencies of these 3 compounds in their actions on such cells in estradiol = 100, 4OHT = 41, tamoxifen = DMT = 2). -
Chronic Exposure to Bisphenol a Reduces SULT1A1 Activity in the Human Placental Cell Line Bewo
Chronic exposure to bisphenol A reduces SULT1A1 activity in the human placental cell line BeWo Pallabi Mitra Department of Pharmaceutical Chemistry University of Kansas October 27, 2006 Outline ▪ Placental structure and models ▪ Placental permeation ▪ Placental metabolism and regulation (induction/inhibition) ▪ Sulfotransferase enzymes in trophoblast ▪ Bisphenol A ▪ Effects of bisphenol A on SULT1A1 ▪ Conclusions The placental barrier The placental barrier Mother’s blood •Trophoblasts and syncytiotrophoblasts line the maternal villar surface in a monolayer- like fashion. •Constitute the rate limiting barrier to exchange between the maternal and fetal blood. Syme et al., Drug transfer and metabolism by the human placenta, Clin Pharmacokinet 2004: 43(8): 487-514 Models of the human placenta ▪ In vivo models – Anatomical and functional differences between mammalian placentas makes it difficult to extrapolate animal studies to humans. ▪ In vitro models ▪ Perfused placental cotyledon ▪ Isolated trophoblast plasma membrane ▪ Isolated transporters and receptors ▪ Villous explants ▪ Primary cultures (cytotrophoblasts) ▪ Immortalized cell lines (BeWo, JAr, JEG, HRP-1, etc.) Refn. Bode et al. In Vitro models for studying trophoblast transcellular transport, Methods Mol Med. 2006;122:225-39 Sastry, B.V., Adv Drug Deliv Rev., 1999 Jun 14. 38(1): p. 17-39. Placental permeation - Factors Efflux Carrier-mediated Passive diffusion transport Metabolism A A X A A Maternal side A X-OH A Fetal side Placental metabolism ▪ Though enzyme expression is much more restricted than hepatic metabolism, those that are functional metabolize xenobiotics as well as hormones. ▪ Placental enzymes CYP1A1/1A2, CYP19 (aromatase), GST, UGT, SULT ▪ Maternal blood-borne chemicals (drugs/polychlorinated biphenyls/pesticides) alter expression and activity. • Altered steroid metabolism. -
Regulation of Xenobiotic and Bile Acid Metabolism by the Anti-Aging Intervention Calorie Restriction in Mice
REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE By Zidong Fu Submitted to the Graduate Degree Program in Pharmacology, Toxicology, and Therapeutics and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Dissertation Committee ________________________________ Chairperson: Curtis Klaassen, Ph.D. ________________________________ Udayan Apte, Ph.D. ________________________________ Wen-Xing Ding, Ph.D. ________________________________ Thomas Pazdernik, Ph.D. ________________________________ Hao Zhu, Ph.D. Date Defended: 04-11-2013 The Dissertation Committee for Zidong Fu certifies that this is the approved version of the following dissertation: REGULATION OF XENOBIOTIC AND BILE ACID METABOLISM BY THE ANTI-AGING INTERVENTION CALORIE RESTRICTION IN MICE ________________________________ Chairperson: Curtis Klaassen, Ph.D. Date approved: 04-11-2013 ii ABSTRACT Calorie restriction (CR), defined as reduced calorie intake without causing malnutrition, is the best-known intervention to increase life span and slow aging-related diseases in various species. However, current knowledge on the exact mechanisms of aging and how CR exerts its anti-aging effects is still inadequate. The detoxification theory of aging proposes that the up-regulation of xenobiotic processing genes (XPGs) involved in phase-I and phase-II xenobiotic metabolism as well as transport, which renders a wide spectrum of detoxification, is a longevity mechanism. Interestingly, bile acids (BAs), the metabolites of cholesterol, have recently been connected with longevity. Thus, this dissertation aimed to determine the regulation of xenobiotic and BA metabolism by the well-known anti-aging intervention CR. First, the mRNA expression of XPGs in liver during aging was investigated. -
Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation
1521-009X/44/4/570–575$25.00 http://dx.doi.org/10.1124/dmd.115.067397 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:570–575, April 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation Abu J. M. Sadeque, Safet Palamar,1 Khawja A. Usmani, Chuan Chen, Matthew A. Cerny,2 and Weichao G. Chen3 Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California Received September 30, 2015; accepted January 7, 2016 ABSTRACT Lorcaserin [(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benza- and among the SULT isoforms SULT1A1 was the most efficient. The zepine] hydrochloride hemihydrate, a selective serotonin 5-hydroxy- order of intrinsic clearance for lorcaserin N-sulfamate is SULT1A1 > Downloaded from tryptamine (5-HT) 5-HT2C receptor agonist, is approved by the U.S. SULT2A1 > SULT1A2 > SULT1E1. Inhibitory effects of lorcaserin Food and Drug Administration for chronic weight management. N-sulfamate on major human cytochrome P450 (P450) enzymes Lorcaserin is primarily cleared by metabolism, which involves were not observed or minimal. Lorcaserin N-sulfamate binds to multiple enzyme systems with various metabolic pathways in human plasma protein with high affinity (i.e., >99%). Thus, despite humans. The major circulating metabolite is lorcaserin N-sulfamate. being the major circulating metabolite, the level of free lorcaserin Both human liver and renal cytosols catalyze the formation of N-sulfamate would be minimal at a lorcaserin therapeutic dose and lorcaserin N-sulfamate, where the liver cytosol showed a higher unlikely be sufficient to cause drug-drug interactions. -
Chemotherapy Regimen: Tamoxifen
Tamoxifen Chemotherapy Teaching The Center for Breast Cancer Mass General Cancer Center Center for Breast Cancer Topics to Discuss: • How Tamoxifen works • How Tamoxifen is taken • Storage, Handling, and Disposal • Drug Interactions • Side Effects & How to Manage • Supportive Care Resources • Your Breast Cancer Team • When to Call • Important Phone Numbers 2 What is TAMOXIFEN? • TAMOXIFEN (Nolvadex®) is an oral hormonal therapy used for hormone-sensitive breast cancers. • It works by blocking estrogen from binding to hormone receptors. This: • decreases the chance of breast cancer returning (recurrence) • decreases tumor size • delays tumors from spreading (progression) • Your care team will talk with you about how long you will need to take this therapy. – It is common to be on therapy for 5-10 years. 3 How is it taken? • TAMOXIFEN is a tablet you take by mouth. • Take one tablet (20 mg) once daily with or without food at the same time each day. – Do not take with grapefruit juice. • Swallow tablet whole with water. Do not break, chew, or crush your tablet. • If you miss a dose, skip the dose. Do not take 2 doses at the same time to make up for the missed dose. 4 Storing and Handling • Keep TAMOXIFEN in its original bottle or in a separate pill box – do not mix other medicines into the same pill box. • Store at room temperature in a dry location away from direct light. • Keep out of reach from children and pets. • Wash your hands before and after handling. – If someone else will be handling your TAMOXIFEN, have them wear gloves so they do not come into direct contact with the medicine. -
Differences Between the Non-Steroidal Aromatase Inhibitors Anastrozole and Letrozole – of Clinical Importance?
British Journal of Cancer (2011) 104, 1059 – 1066 & 2011 Cancer Research UK All rights reserved 0007 – 0920/11 www.bjcancer.com Minireview Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance? ,1 J Geisler* 1 Institute of Clinical Medicine, University of Oslo, Faculty Division at Akershus University Hospital, Sykehusveien 27, Lørenskog N-1478, Norway Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; ‘FACE-trial’), clinicians have to make their choices today. -
Tamoxifen Metabolite Testing
Tamoxifen Metabolite Testing Tamoxifen (Tam) , the anti-estrogen used to treat seen in active metabolites. The Anti-estrogenic activity estrogen receptor (ER)-positive breast cancer, is a score (ASS) was developed, based on the plasma pro-drug that is converted to its therapeutically active active isomer concentrations and their respective metabolites, Z- and Z’-endoxifen isomers and Z- and antiestrogenic activities, to arrive at a more accurate Z’-4-hydroxy-tamoxifen (Z-4-OH-Tam) isomers by several estimate of the biologic eectiveness of Tam metabolic enzymes. Both Z-endoxifen and Z-4-OH-Tam treatment 2. Both Tam metabolite testing and CYP2D6 have an ~100-fold greater anity towards the ER and a genotyping are oerred together at Mount Sinai Genetic 30- to 100-fold greater potency in suppressing estrogen- Testing Laboratory for personalized Tam treatment. dependent cell proliferation than Tam, whereas the Z’ isomers of endoxifen and 4-OH-Tam have ~10% of their respective Z isomer activity levels 1. Eective treatment depends on adequate Tam conversion to its active metabolite isomers. The plasma active metabolite concen- trations vary due to several factors: common genetic variants in genes encoding the biotransformation enzymes (e.g., CYP2D6), environmental factors that inhibit these enzymes (e.g., concomitant drugs), and compliance to the medication. The polymorphic CYP2D6 enzyme is critical in the Tam conversion to Z-endoxifen; however, CYP2D6 Figure: Schema of tamoxifen biotransformation in (a) CYP2D6 extensive genotype can only account for 30% – 40% of the variability and ultra-rapid metabolizers and (b) CYP2D6 poor metabolizers. Testing Methods, Sensitivity and Turnaround Time: tion is available at Mount Sinai Genetic Testing Labora- Biochemical analysis: Mount Sinai Genetic Testing tory and should be ordered the first time blood is drawn Laboratory is the only clinical lab that oers Tam for metabolite testing. -
Effect of Tamoxifen Or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer
ANTICANCER RESEARCH 31: 1367-1372 (2011) Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer S.J. STANWAY1, C. PALMIERI2, F.Z. STANCZYK3, E.J. FOLKERD4, M. DOWSETT4, R. WARD2, R.C. COOMBES2, M.J. REED1† and A. PUROHIT1 1Oncology Drug Discovery Group, Section of Investigative Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, U.K.; 2Cancer Research UK Laboratories, Department of Oncology, Hammersmith Hospital, London W12 0NN, U.K.; 3Reproductive Endocrine Research Laboratory, University of Southern California, Keck School of Medicine, Women’s and Children’s Hospital, Los Angeles, CA, U.S.A.; 4Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, U.K. Abstract. Background: In postmenopausal women sulfate and dehydroepiandrosterone levels. Results: Neither estrogens can be formed by the aromatase pathway, which anastrozole nor tamoxifen had any significant effect on STS gives rise to estrone, and the steroid sulfatase (STS) route activity as measured in PBLs. Anastrozole did not affect which can result in the formation of estrogens and serum androstenediol concentrations. Conclusion: androstenediol, a steroid with potent estrogenic properties. Anastrozole and tamoxifen did not inhibit STS activity and Aromatase inhibitors, such as anastrozole, are now in serum androstenediol concentrations were not reduced by clinical use whereas STS inhibitors, such as STX64, are still aromatase inhibition. As androstenediol has estrogenic undergoing clinical evaluation. STX64 was recently shown properties, it is possible that the combination of an to block STS activity and reduce serum androstenediol aromatase inhibitor and STS inhibitor may give a therapeutic concentrations in postmenopausal women with breast cancer.