DOCSLIB.ORG

O O O Castrate Control COHP24 O (57) Abstract: Disclosed Herein Are Compositions and Methods for Modulating the Androgen Receptor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
O O O Castrate Control COHP24 O (57) Abstract: Disclosed Herein Are Compositions and Methods for Modulating the Androgen Receptor (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/041040 Al 9 March 2017 (09.03.2017) P O PCT (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 215/38 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 16/050270 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 2 September 2016 (02.09.2016) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 62/214,613 4 September 2015 (04.09.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: CITY OF HOPE [US/US]; 1500 E. Duarte TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Road, Duarte, CA 91010-3000 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: JONES, Jeremy; 3235 Las Lunas Street, Pas SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, adena, CA 9 1107 (US). PAL, Sumanta, Kumar; 2496 W. GW, KM, ML, MR, NE, SN, TD, TG). Kern River Lane, Brea, CA 92821 (US). Published: (74) Agents: TERRANOVA, Zachary, L. et al; Mintz Levin Cohn Ferris Glovsky And Popeo, P.C., 3580 Carmel — with international search report (Art. 21(3)) Mountain Road, Suite 300, San Diego, CA 92 130-6768 — with sequence listing part of description (Rule 5.2(a)) (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: ANDROGEN RECEPTOR ANTAGONISTS 22Rvl xenograft o o o Castrate control COHP24 o (57) Abstract: Disclosed herein are compositions and methods for modulating the androgen receptor. o ANDROGEN RECEPTOR ANTAGONISTS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/214,613, filed September 4, 20 5, which is incorporated herein by reference in its entirety for all purposes. REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE [0002] The Sequence Listing written in file 48440-546001WO_ST25.TXT, created September 2, 2016, 55,151 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference. BACKGROUND [0003] Androgen receptor (A l ) is a member of the nuclear hormone receptor family activated by androgens, such as dihydrotestosterone (DHT). AR is a prime therapeutic target for treating prostate cancer. Several compounds have been developed as chemotherapy for prostate cancer. [0004] Androgen receptor competitive antagonists (antiandrogens) are drugs used to treat hormonal-based syndromes and prostate cancer. Current drugs for prostate cancer include flutamide, bicaiutamide, nilutamide, enzalutaraide and ARN-509. Each of these inhibitors binds to the hormone-binding pocket (HBP) of the androgen receptor. This is the same site that the natural physiological steroids testosterone (TES) and dihydrotestosterone (DHT) bind. The drugs work by competing with the natural hormones for binding to the pocket and, as a result, lessening activation of the receptor. Androgen receptor antagonists with different mechanisms of action and/or different binding sites would be complementary to the current commercially available antagonists. [0005] Disclosed herein are solutions to these and other problems in the art. BRIEF SUMMARY 0006] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: 0007] R is hydrogen or substituted or unsubstituted pyrid-2-yi. R is independently a 2 2 , 2 10 8 8 hydrogen, halogen, -CX 3, -CHX -CH 2X , -CN, -S 2 R , -SO 2 NR R , -NHNR R , 8 8 8 9 -ONR R , M IC (}} !i\ ---NH ( (0 ) R R , -N(0) RA2 , -NR R , -C(0)R , 9 7 8 10 ~ 9 9 9 -C(0)~OR , -C(0)NR R , -OR , -NR SO2R , -N C (0)R , -NR C(0)-QR , -NR OR , 2 -OCX 3, -OCHX 2, -O substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkvl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkvl, substituted or unsubstituted aryf, or substituted or unsubstituted heteroaryl. R3 3 14 12 is independently a hydrogen, halogen, -CX , -CHX 2, -CH2X , -CN, -SQ„ R , -SO NR R , 12 ~ -NHNH 2, -ONR R , NHC=(0)NHNH 2, 2 2 13 1 -NHC=(0)NR R , -N(0) FFI3 , -NR R , -C(0)R , -C(0)OR , O -OR 14, -NR S0 R14, -NR C= (O)R 13, -NR C(0)-OR 13, -NR OR 13, 3 -OCX , -OCHX 2, OCH X , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkvl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkvl, substituted or unsubstituted aryi, or substituted or unsubstituted heteroaryl. R 7, R8, R9, R 10 , R 11, R 2 , R 13, and R 1 are independently hydrogen, halogen, -CX3, -CHX2, -CH 2X , -OCX3, -OCHX2, -OCH 2X , -CN, -OH, -NH 2, -COOH, -CONH2 , -N0 2, -Si , -S0 H , -SO4H, -S N -NHNH 2, -ONH 2, M IC (0 X W W () N H2, -NHS0 2H , ~\ (0)H, -NHC(0)-OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkvl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkvl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 and R8 substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocvcloalkyl or substituted or unsubstituted heteroaryl; R and R 2 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryi. R4 is independently 4 4 hydrogen, a -CX , -CHX 2, -CH2X , -CN, -C(G)H, -C(0)OH, -C(0)NH 2, substituted or unsubstituted a ky , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryi. R5 is independently a hydrogen, 5 halogen, X -CHX , -CH X , -CN, -C(0)H, -0 , 0 ! , -C(0)NH 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryi. R6 is independently a hydrogen, halogen, -CX , -C¾X 6, -CN, -C(0)H, -C(0)OH, -C(0)N¾, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cvcloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryi. L is independently a bond, substituted or unsubstituted aikyiene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkvnylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted heteroalkenylene, or substituted or unsubstituted heteroalkynylene. The symbols ml, m3, v2, and v3 are independently 1 or 2 . The symbols n2 and n3 are independently an integer from 0 to 4 . X, X2, X3, X4, X5, and X6 are independently -CI, -Br, -I, or -F. [0008] In another aspect is provided a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, as described herein. ] In another aspect is provided a method of treating a nuclear receptor activity-associated disease in a subject in need of such treatment, the method including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein. [0010] In another aspect is provided a method of treating cancer in a subject in need of such treatment, the method including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein. [0011] In another aspect is provided a method of inhibiting androgen receptor activity in a subject in need thereof, including administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof. [0012] In another aspect is provided a method of inhibiting androgen receptor activity, the method including contacting an androgen receptor with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1. Inhibition of AR activity in LNCaP cells. LNCaP cells were transfected with PSA-luciferase and a reniila control plasmid. The following day, quadruplicate wells were treated with 0.3nM DHT and increasing concentrations of the indicated compound, or vehicle. Luciferase activity was assayed 24 hours later, and the renilla-normalized PSA-luciferase activity s shown. [0014] FIG. 2 . LNCaP prostate cancer cells were grown for 7 days in the presence of the indicated compound (BiC = bicalutamide) and relative growth was assayed by D PI staining of fixed ceils and fluorescence measurement on a plate reader. Bars represent the standard error of conditions tested in quadruplicate [0015] FIG. 3 . Luciferase assay IC 0 determination and synergy with bicalutamide. See Example 2 . [0016] FIGS. 4A-4B. Activity against AR splice variants. FIG. 4A: AR-V7; FIG. 4B: A -V & es. See Example 3 . [0017] FIG. 5. Inhibition of xenograft growth in vivo; Y-axis: relative growth with respect to initial tumor size. Assay conditions (left to right): control, castrate, COHP7, and COHP24.
Load more

Recommended publications
  • Failures and Controversies of the Antiestrogen Treatment of Breast Cancer
    In: Estrogen Prevention for Breast Cancer ISBN: 978-1-62417-378-3 Editor: Zsuzsanna Suba © 2013 Nova Science Publishers, Inc. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Chapter VII Failures and Controversies of the Antiestrogen Treatment of Breast Cancer Zsuzsanna Suba National Institute of Oncology, Department of Surgical and Molecular Pathology, Budapest, Hungary Abstract In postmenopausal women, estrogens have unquestionable preventive and curative effects against atherogenic cardiovascular lesions, osteoporosis and neurodegenerative diseases. Moreover, recent studies on correlations between hormone replacement therapy and cancer risk could justify preventive, anticancer capacities of estrogen both on smoking associated and hormone related cancers. Experimental developing of antiestrogen compounds aimed to inhibit the binding of presumably harmful, endogenous estrogen to its receptor system so as to achieve a regression of hormone-related cancers. However, antiestrogens proved to be ineffective in the majority of selected receptor positive breast cancer cases and produced severe side effects, such as vascular complications and cancer development at several sites. Failure of antiestrogen therapy was designated as ―endocrine resistance‖ of tumors.
    [Show full text]
  • NDA/BLA Multi-Disciplinary Review and Evaluation
    NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) NDA 214154 (IND 110682) Priority or Standard Standard Submit Date(s) April 15, 2020 Received Date(s) April 15, 2020 PDUFA Goal Date April 15, 2021 Division/Office Division of Urology, Obstetrics, and Gynecology (DUOG) / Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM) Review Completion Date April 15, 2021 Established/Proper Name drospirenone and estetrol tablets (Proposed) Trade Name Nextstellis Pharmacologic Class Combination hormonal contraceptive Applicant Mayne Pharma LLC Dosage form Tablet Applicant proposed Dosing x Take one tablet by mouth at the same time every day. Regimen x Take tablets in the order directed on the blister pack. Applicant Proposed For use by females of reproductive potential to prevent Indication(s)/Population(s) pregnancy Recommendation on Approval Regulatory Action Recommended For use by females of reproductive potential to prevent Indication(s)/Population(s) pregnancy (if applicable) Recommended Dosing x Take one pink tablet (drospirenone 3 mg, estetrol Regimen anhydrous 14.2 mg) by mouth at the same time every day for 24 days x Take one white inert tablet (placebo) by mouth at the same time every day for 4 days following the pink tablets x Take tablets in the order directed on the blister pack 1 Reference ID: 4778993 NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) Table of Contents Table of Tables .................................................................................................................... 5 Table of Figures ................................................................................................................... 7 Reviewers of Multi-Disciplinary Review and Evaluation ...................................................
    [Show full text]
  • A Phosphotyrosyl Peptide That Blocks Dimerization of the Human Estrogen Receptor (Estradiol/MCF-7 Cells/Tyrosine Phosphorylation/Dimerization/DNA Binding) STEVEN F
    Proc. Natl. Acad. Sci. USA Vol. 92, pp. 7475-7479, August 1995 Biochemistry An antiestrogen: A phosphotyrosyl peptide that blocks dimerization of the human estrogen receptor (estradiol/MCF-7 cells/tyrosine phosphorylation/dimerization/DNA binding) STEVEN F. ARNOLD AND ANGELO C. NOTIDES* Departments of Environmental Medicine and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 Communicated by Jack Gorski, University of Wisconsin, Madison, WI, April 28, 1995 (received for review January 13, 1995) ABSTRACT We have previously identified tyrosine-537 scription (STAT) bind DNA as dimers through a reciprocal as a constitutively phosphorylated site on the human estrogen association of a phosphotyrosine on one monomer with a Src receptor (hER). A 12-amino acid phosphotyrosyl peptide homology 2 domain (SH2 domain) on the complementary containing a selected sequence surrounding tyrosine-537 was monomer (15, 16). used to investigate the function of phosphotyrosine-537. The Deletion and mutational analyses have provided evidence phosphotyrosyl peptide completely blocked the binding of the that the C terminus of the steroid hormone receptors is hER to an estrogen response element (ERE) in a gel mobility necessary for receptor dimerization (4). The dimerization of shift assay. Neither the nonphosphorylated tyrosyl peptide the nuclear hormone receptors is reported to be regulated by nor an unrelated phosphotyrosyl peptide previously shown to hydrophobic heptad repeats in the C terminus (17, 18). A inhibit the signal transducers and activators of transcription 22-amino acid sequence from positions 501 to 522 in the C factor (STAT) blocked binding of the hER to the ERE. The terminus of the mouse estrogen receptor was isolated that hER phosphotyrosyl peptide was shown by molecular sizing conferred DNA binding to DNA-binding-deficient mutants chromatography to dissociate the hER dimer into monomers.
    [Show full text]
  • Use of Aromatase Inhibitors in Breast Carcinoma
    Endocrine-Related Cancer (1999) 6 75-92 Use of aromatase inhibitors in breast carcinoma R J Santen and H A Harvey1 Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA 1Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA (Requests for offprints should be addressed to R J Santen) Abstract Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH andro- stenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross- resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone- dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents.
    [Show full text]
  • Network-Based Characterization of Drug-Protein Interaction Signatures
    Tabei et al. BMC Systems Biology 2019, 13(Suppl 2):39 https://doi.org/10.1186/s12918-019-0691-1 RESEARCH Open Access Network-based characterization of drug-protein interaction signatures with a space-efficient approach Yasuo Tabei1*, Masaaki Kotera2, Ryusuke Sawada3 and Yoshihiro Yamanishi3,4 From The 17th Asia Pacific Bioinformatics Conference (APBC 2019) Wuhan, China. 14–16 January 2019 Abstract Background: Characterization of drug-protein interaction networks with biological features has recently become challenging in recent pharmaceutical science toward a better understanding of polypharmacology. Results: We present a novel method for systematic analyses of the underlying features characteristic of drug-protein interaction networks, which we call “drug-protein interaction signatures” from the integration of large-scale heterogeneous data of drugs and proteins. We develop a new efficient algorithm for extracting informative drug- protein interaction signatures from the integration of large-scale heterogeneous data of drugs and proteins, which is made possible by space-efficient representations for fingerprints of drug-protein pairs and sparsity-induced classifiers. Conclusions: Our method infers a set of drug-protein interaction signatures consisting of the associations between drug chemical substructures, adverse drug reactions, protein domains, biological pathways, and pathway modules. We argue the these signatures are biologically meaningful and useful for predicting unknown drug-protein interactions and are expected to contribute to rational drug design. Keywords: Drug-protein interaction prediction, Drug discovery, Large-scale prediction Background similar drugs are expected to interact with similar pro- Target proteins of drug molecules are classified into a pri- teins, with which the similarity of drugs and proteins are mary target and off-targets.
    [Show full text]
  • Editorial.Final 10/20/06 1:39 PM Page 10
    OBG_11.06_Editorial.final 10/20/06 1:39 PM Page 10 EDITORIAL Is Premarin actually a SERM? It acts like a SERM... onjugated equine estrogen Effects of tamoxifen and Premarin (Premarin) has historically been Initially, tamoxifen was characterized as an C characterized as an estrogen ago- “anti-estrogen,” but it is now recognized nist. But the report from the Women’s that tamoxifen has mixed properties. It is an Health Initiative that long-term Premarin estrogen antagonist in some tissues (breast) Robert L. Barbieri, MD Editor-in-Chief treatment is associated with a reduced risk and an estrogen agonist in other tissues of breast cancer raises the possibility that (bone). To recognize these mixed estrogen Premarin may have both estrogen agonist agonist–antagonist properties, tamoxifen is and antagonist properties. Premarin may now categorized as a SERM. Premarin and actually be better categorized as a selective tamoxifen share many similarities in their estrogen receptor modulator (SERM). effects on major clinical outcomes in post- ® Dowden Healthmenopausal Media women (Table, page 13), WHI: Premarin vs placebo including their effects on breast and In the Premarin vs placebo arm, approximately endometrial cancer, deep venous thrombo- 10,800Copyright postmenopausalFor personal women with ause prior onlysis, and osteoporotic fracture. One clinical- hysterectomy who were 50 to 79 years of age ly important divergence is that tamoxifen were randomized to Premarin 0.625 mg daily or increases and Premarin decreases vasomo- an identical-appearing placebo.1 After a mean tor symptoms. FAST TRACK follow-up of 7.1 years, the risk of invasive breast Commonly used medications that inter- In any case, cancer in the women treated with Premarin was act with the estrogen receptor can be 0.80 (95% confidence interval [CI], 0.62–1.04, arranged along a continuum from a “pure” “Use the lowest P=.09).
    [Show full text]
  • Characterization and Quantitation of Antiestrogen Binding Sites in Estrogen Receptor-Positive and -Negative Human Breast Cancer Cell Lines1
    (CANCER RESEARCH 43, 3094-3100, July 1983] Characterization and Quantitation of Antiestrogen Binding Sites in Estrogen Receptor-positive and -negative Human Breast Cancer Cell Lines1 Margaret Ann Miller and Benita S. Katzenellenbogen2 Department ol Physiology and Biophysics, University of Illinois, and University of Illinois College of Medicine, Urbana, Illinois 61801 ABSTRACT gens. It is possible, however, that these antiestrogen binding sites might influence the distribution of antiestrogens and, hence, Antiestrogens are useful in the treatment of endocrine-respon their accessibility to estrogen receptor in estrogen receptor- sive breast cancers in humans. In an attempt to understand the positive cells, or they might mediate actions of antiestrogens mechanisms underlying their estrogen antagonism and antitumor that are unrelated to estrogen antagonism. character, we have examined the interaction of antiestrogens with three human breast cancer cell lines that differ markedly in INTRODUCTION their estrogen receptor content and in their sensitivity to growth suppression by antiestrogens. MCF-7 cells have high levels of Antiestrogens are intriguing compounds that are able to an estrogen receptor, and their growth is inhibited markedly by tagonize many of the effects of estrogens. Although these non- antiestrogens; T47D cells contain low levels of estrogen recep steroidal triphenylethylene compounds were developed initially tor, and their growth is suppressed weakly by antiestrogens; by pharmaceutical companies as fertility-regulating agents, they and MDA-MB-231 cells contain no detectable estrogen recep are of particular interest and importance today because of their tors, and their growth is unaffected by antiestrogens. In addition clinical efficacy in controlling the growth and spread of hormone- to binding to the estrogen receptor, antiestrogens are found to dependent mammary and uterine tumors; with them, it appears be associated with binding sites that are distinct from the estro to be possible to achieve noninvasively the same hormonal gen receptor.
    [Show full text]
  • TEDX the Endocrine Disruption Exchange 211 Grand Ave, Ste. 114, P.O
    TEDX The Endocrine Disruption Exchange 211 Grand Ave, Ste. 114, P.O. Box 1407, Paonia, CO 81428 970-527-4082 [email protected] References Acevedo HF, Tong JY, Hartsock RJ. 1995 . Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins. Cancer 76:1467-1475. Abstract: BACKGROUND. The authors' previous investigations using living cultured human cancer cells and cells isolated from cancer tissues, analytical flow cytometry, and monoclonal antibodies directed to epitopes located in five different sites of the human chorionic gonadotropin (hCG) molecule, identified the presence of membrane-associated hCG, its subunits and fragments, by cells from all cancers, irrespective of type and origin, indicating that the expression of these sialoglycoproteins is a common phenotypic characteristic of cancer. Although benign neoplasms do not express these compounds, cultured human embryonic and fetal cells also express the same materials. To corroborate these findings, five fetal cell lines and 28 cancer cell lines were randomly selected from those previously studied, to determine the presence of translatable levels of hCG-beta (hCG beta) mRNA. METHODS. All cell lines were grown under identical conditions. Determination of hCG beta mRNA was made by extracting the total RNA from the cells, followed by synthesis of cDNA with RNase H- reverse transcriptase and polymerase chain reaction amplification using specific hCG beta-luteinizing hormone-beta (hLH beta) primers. The presence of amplified hCG beta cDNA was corroborated by hybridization of the product with an hCG beta-specific oligonucleotide and Southern blot analyses of the hybridization products. Gestational choriocarcinoma cells and HeLa adenocarcinoma of cervical cells, known producers of biologically active hCG, were positive control subjects, and human pituitary cells were used as negative control subjects.
    [Show full text]
  • Review Therapeutic Options for Management of Endometrial
    Review Therapeutic Options for Management of Endometrial Hyperplasia: An Update Vishal Chandraa,c* , Jong Joo Kim b*, Doris Mangiaracina Benbrooka, Anila Dwivedic, Rajani Raib aUniversity of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. bSchool of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk, 712-749, Korea. cDivision of Endocrinology, CSIR- Central Drug Research Institute, Lucknow-226031, U.P., India. *Both authors contributed equally to this work Shortened Title: Endometrial hyperplasia and therapy Corresponding author: Rajani Rai School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk, 712-749, Korea Tel: +821064640764 E-mail: [email protected], [email protected] Received 25 Jun, 2015 Revised 24 Jul, 2015 Accepted 31 Jul, 2015 1 Abbreviations: Body mass index (BMI), chemokine (C-C motif) ligand 2 (CCL2), confidence interval (CI), danazol containing intrauterine device (D-IUD), endometrial cancer (EC), endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), estrogen receptor (ER), gonadotropin-releasing hormone (GnRH), levonorgestrel-impregnated intrauterine device (LNG-IUS), medroxy-progesterone acetate (MPA), megestrol acetate (MA), levonorgestrel (LNG), odds ratio (OR), polycystic ovarian syndrome (PCOS) selective estrogen receptor modulators (SERMs), World Health Organization (WHO), continuous-combined hormone replacement therapy (CCHRT), progestron receptor (PR) Vascular endothlial growth factor (VEGF), epidermal growth factor receptor (EGFR), mechanistic target of
    [Show full text]
  • Antiestrogen ICI 164,384 Reduces Cellular Estrogen Receptor Content by Increasing Its Turnover SOPHIE DAUVOIS, PAUL S
    Proc. Natl. Acad. Sci. USA Vol. 89, pp. 4037-4041, May 1992 Biochemistry Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover SOPHIE DAUVOIS, PAUL S. DANIELIAN, ROGER WHITE, AND MALCOLM G. PARKER* Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom Communicated by Elwood V. Jensen, December 30, 1991 (received for review August 21, 1991) ABSTRACT The ability of estrogens to stimulate the tran- with a subsequent step required for receptor-mediated gene scriptional activity of the estrogen receptor can be inhibited by transcription (16, 17). a diverse range of estrogen antagonists. Here we show that the The variation in the ability of ICI 164,384 to inhibit the antiestrogen ICI 164,384, N-(n-butyl)-11-[3,1713-dihydroxy- DNA binding activity of the estrogen receptor might be estra-1,3,5(10)-trien-7a-yl]N-methylundecanamide, rapidly explained by differences in the stability of receptor dimers. reduces the levels of receptor protein transiently expressed in Since it may not always be possible to dissociate preformed cells without affecting receptor mRNA abundance. The reduc- dimers and inhibit DNA binding in cell-free extracts, we have tion in the levels of receptor protein is dose dependent, revers- investigated whether ICI 164,384 was able to prevent DNA ible by estradiol, and mediated by the hormone-binding do- binding in intact cells. In this paper we show that ICI 164,384 main ofthe receptor. Pulse-chase experiments indicate that the treatment causes a decrease in cellular content of estrogen half-life of the receptor is reduced from -5 hr in the presence receptor protein by markedly reducing its half-life and sug- of estradiol to <1 hr by ICI 164,384.
    [Show full text]
  • Hormorial Therapy in the Management of Premenstrual Syndrome
    J Am Board Fam Pract: first published as 10.3122/15572625-11-5-378 on 1 September 1998. Downloaded from MEDICAL PRACTICE Hormorial Therapy in the Management of Premenstrual Syndrome Jeffrey D. Tiemstra, MD, and Krishna Patel, PharmD Background: Premenstrual syndrome (PMS) is characterized by any of a number of physical and psychological symptoms consistently occurring in the late luteal phase. Progesterone therapy is often recommended based on anecdotal evidence, although controlled studies have shown it to be ineffective. Oral contraceptives are more often used with mixed results. When hormonal therapy for PMS is indicated, the most appropriate choice remains a challenge. Methods: We describe a case report of successful hormonal therapy for PMS and a review of the literature on the effectiveness of hormonal therapies. Results and Conclusimls: Estrogen is clearly effective in relieving 'symptoms of PMS, whereas progesterone is ineffective and might even worsen symptoms. Combination oral contraceptives are effective, undoubtedly as a result of the estrogen component. While little comparative data exist to guide choice of an oral contraceptive, maximizing the relative estrogenic potency of the oral contraceptive seems logical. Depressive symptoms might not respond to hormonal treatment, and new research suggests that selective serotonin reuptake inhibitors might be particularly effective. 0 Am Board Pam Pract 1998;11:378-81.) Premenstrual syndrome (PMS), also referred to as elimination of caffeine, biofeedback, and relaxation late luteal phase dysphoric disorder, is a problem therapy. Because the beneficial effects of these copyright. commonly encountered in primary care, with up measures have not been proved, patients who seek to 10 percent of women of childbearing age experi­ medical attention for this syndrome will usually re­ encing symptoms severe enough to seek medical quire pharmacologic treatments.
    [Show full text]
  • Fulvestrant As a Reference Antiestrogen and Estrogen Receptor
    4468 Editorial Commentary Fulvestrant as a reference antiestrogen and estrogen receptor (ER) degrader in preclinical studies: treatment dosage, efficacy, and implications on development of new ER-targeting agents Guangdi Wang RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA Correspondence to: Guangdi Wang. RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. Email: [email protected]. Provenance and Peer Review: This article was commissioned by the editorial office,Translational Cancer Research. The article did not undergo external peer review. Comment on: Wardell SE, Yllanes AP, Chao CA, et al. Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy. Breast Cancer Res Treat 2020;179:67-77. Submitted Jun 01, 2020. Accepted for publication Jun 30, 2020. doi: 10.21037/tcr-20-2166 View this article at: http://dx.doi.org/10.21037/tcr-20-2166 Endocrine therapy remains the standard of care for with CDK4/6 inhibitors for metastatic/advanced breast hormone receptor positive (HR+), HER2 negative (HER2−) cancer (5). breast cancer. Clinically approved endocrine agents Fulvestrant was developed as a pure antiestrogen include selective estrogen receptor modulators (SERMs), by modification of long-chain alkyl substitutes in the aromatase inhibitors (AIs), and selective estrogen receptor 7α-position of estradiol (6,7). The steroidal antiestrogen downregulators/degraders (SERDs). These therapeutic was shown to have no estrogen receptor agonist or regimens are well tolerated with manageable side effects partial agonist effects in any species or organ where other and have proven effective in early stage breast cancer with antiestrogens show tissue-selective agonistic activities curative intent.
    [Show full text]