DOCSLIB.ORG

Aromatase Inhibitors As Potential Cancer Chemopreventives

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Aromatase Inhibitors As Potential Cancer Chemopreventives V Vol. 7, 65-78, Januar’, 1998 Cancer Epidemiology, Biomarkers & Prevention 65 Review Aromatase Inhibitors as Potential Cancer Chemopreventives Gary J. Kelloff,t Ronald A. Lubet, Ronald Lieberman, local estrogen production may be an alternative strategy, Karen Eisenhauer, Vernon E. Steele, James A. Crowell, as suggested by the discovery of a unique transcriptional Ernest T. Hawk, Charles W. Boone, and promoter of aromatase gene expression, 1.4, in breast Caroline C. Sigman adipose tissue. The development of drugs that target this Chemoprevention Branch, Division of Cancer Prevention and Control, promoter region may be possible. National Cancer Institute, Bethesda, Maryland 20852 1G. J. K., R. A. L., R. L.. V. E. S., J. A. C., E. T. H., C. W. B.l; and CCS Associates, Mountain View, Califomia 94043 1K. E., C. C. S.] Strategies in Development of Cancer Chemopreventive Agents This paper is the third in a series on strategies used by the Abstract Chemoprevention Branch of the National Cancer Institute to Epidemiological and experimental evidence strongly develop cancer chemoprevention drugs ( 1-3). One chemopre- supports a role for estrogens in the development and ventive strategy for hormone-dependent cancers is to interfere growth of breast tumors. A role for estrogen in prostate with the hormones that stimulate cellular proliferation in these neoplasia has also been postulated. Therefore, one tumors. Among the most important of these targets for inter- chemopreventive strategy for breast and prostate cancers vention are estrogen-responsive tumors. Estrogen production is to decrease estrogen production. This can be can be decreased by inhibiting aromatase, the enzyme cata- accomplished by inhibiting aromatase, the enzyme that lyzing the final, rate-limiting step in estrogen biosynthesis. The catalyzes the final, rate-limiting step in estrogen use of aromatase inhibitors is of clinical interest for cancer biosynthesis. The use of aromatase inhibitors is of clinical therapy, and selective, potent aromatase inhibitors have been interest for cancer therapy, and selective, potent developed. The rationale for use of aromatase inhibitors as aromatase inhibitors have been developed. Several of chemopreventives and identification of inhibitors to serve as these agents have demonstrated chemopreventive efficacy potential cancer chemopreventive agents are the subjects of this in animal models. review. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve Association of Estrogen with Carcinogenesis as potential chemopreventive agents are the subjects of Breast. Aromatase, the enzyme that catalyzes the rate-limiting this review. After background information regarding step in estrogen formation (4), is expressed in several tissues in aromatase is presented, the data for each inhibitor are women. In premenopausal women, the granulosa cells of ovar- summarized separately. The discussion focuses on those ian follicles produce the majority of circulating estrogen, pri- inhibitors that are clinically available or in clinical trials, marily in the form of estradiol. Estrogen is also produced including: aminoglutethimide (Cytadren), rogletimide, extragonadally in liver, muscle, and fat by aromatization of fadrozole hydrochloride, liarozole hydrochloride, adrenal androgens. After menopause, adipose tissue is the ma- anastrozole (Arimidex), letrozole, vorozole, formestane, jor source ofcirculating estrogens (5). Extragonadal production exemestane, and atamestane. On the basis of results from of estrogen primarily involves aromatization of adrenal andro- preclinical studies, aromatase inhibitors may be stenedione, resulting in estrone, a weaker estrogen than estra- promising agents for clinical trials in populations at high diol (6). Epidemiological evidence strongly supports a role for risk for developing estrogen-dependent cancers. estrogens in the development and growth of breast neoplasia. Total suppression of aromatase may have adverse The most consistently documented epidemiological risk factors effects, as is evident in postmenopausal women (increased for breast cancer, early age at menarche, late age at menopause, osteoporosis, cardiovascular disease, and urogenital late age at first full-term pregnancy, and postmenopausal atrophy). However, on the basis of precinical studies of weight gain, all increase cumulative endogenous estrogen ex- chemopreventive efficacy and chemotherapeutic posure (7-9). Experimental evidence also strongly favors a role applications of aromatase inhibitors showing dose- for estrogens in the development and growth of breast cancers response efficacy, it may be possible to obtain ( 10, 1 1 ). Estrogens promote the development of mammary chemopreventive effects without total suppression of cancer in rodents and exert both direct and indirect proliferative aromatase and circulating estrogen levels. Suppressing effects on cultured breast cancer cells ( 1 1 ). Induction of en- zymes and proteins involved in nucleic acid synthesis (e.g., DNA polymerase and thymidine kinase) and oncogenes may account for their direct mitogenic effects. Indirect effects of Received 6/6/97; revised 9/29/97; accepted 10/15/97. The costs of publication of this article were defrayed in part by the payment of these hormones also occur via induction of pituitary prolactin page charges. This article must therefore be hereby marked advertisement in secretion and expression of various growth factors (e.g. , trans- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. forming growth factor a and epidermal growth factor) and I To whom requests for reprints should be addressed, at Chemoprevention non-growth factor peptides (e.g. , plasminogen activators). It Branch, Division of Cancer Prevention and Control, National Cancer Institute, Executive Plaza North, Suite 201, 6130 Executive Boulevard, Rockville, MD has been estimated that 30% of breast cancers are dependent on 20852. estrogen for their proliferation ( 1 2, 13). Although the available Downloaded from cebp.aacrjournals.org on September 29, 2021. © 1998 American Association for Cancer Research. 66 RevIew: Aromatase Inhibitors as Cancer Chemopreventives data are not conclusive, there is also evidence that estrogens induce regression of established tumors (e.g. , 28, 29) and, more may be directly genotoxic, for example, by DNA alkylation or importantly for the purposes of this discussion, prevent cancer oxidation, leading to free radicals, which, in turn, bind to and development (27, 30, 31). damage DNA (e.g., Ref. 14). Prostate. Etiological and risk factors for prostate cancer in- The estrogen that stimulates tumor growth can be derived dude age of >50 years, family history, high serum testoster- from extratumoral or tumor sources, and the relative impor. one, high-fat diet, prostatitis, and geographical background tance of each is controversial. Within the breast, adipose tissue (prevalence being highest in the United States, Canada, and is the major extratumoral source of aromatase, although aro- northwest Europe; Ref. 32). As for breast cancer, significant matase was also detected immunocytochemically in normal risk for prostate cancer appears to be associated with exposure breast epithelial cells in one study (15). Aromatase activity is to steroid hormones (i.e. , the high serum testosterone and high higher in adipose tissue from breast cancer patients than it is fat consumption). Besides testosterone, estrogens have also from those with benign breast disease (16). In breasts with been postulated to play a role in prostate cell proliferation and cancer, aromatase expression (17) and activity (18) are higher have been implicated in BPH and prostate cancer. BPH is a in quadrants bearing tumors compared with those without tu- nonmalignant enlargement of the prostate due to cellular hy- mors. The exact cellular localization of aromatase expression in perplasia and hypertrophy of both the epithelial and stromal breast cancer tissue is also somewhat controversial. Immuno- elements of the gland, whereas prostate cancer involves the cytochemical studies have detected aromatase in breast carci- epithelial tissue. Studies on the role of estrogen in BPH may be noma cells ( 15, 19) and in stromal spindle cells in breast tumors informative about the regulation of prostate cell proliferation, (20). At the present time, it appears that both adipose and breast but it should be emphasized that prostatic intraepithelial neo- tumor cells contribute to locally high estrogen production, and plasia, not BPH, is the most likely precursor of prostate carci- determination of their relative importance requires further noma (33, 34). study. In men, 10-25% of estrogen is synthesized locally in the The effects of estrogens are mediated by the ER.2 Al- testes, and 75-90% arises from extraglandular aromatization of though only a few studies have been carried out, 100% of testosterone and androstenedione (5, 35). The estrogen:andro- precancerous atypical hyperplastic ductal breast lesions that gen ratio increases with age, presumably due to greater estrogen have been studied express ER (21), and ER levels are higher in synthesis, accompanied by unchanged or decreased androgen atypical ductal hyperplasia than they are in normal breast epi- production. Whether the prostate is a source of estrogen is thelium (22). Changes in ER expression during tumor progres- controversial. Some studies have reported an absence of aro- sion are not well established,
Load more

Recommended publications
  • The Effects of Targeted Deletion of the Aromatase Enzyme on Prostatic Contractile Responses to Noradrenaline in Mice
    495 The effects of targeted deletion of the aromatase enzyme on prostatic contractile responses to noradrenaline in mice Katherine T Gray, Jennifer L Short, Evan R Simpson1 and Sabatino Ventura Prostate Research Co-operative, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia 1Prince Henry’s Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia (Correspondence should be addressed to S Ventura; Email: [email protected]) Abstract This investigation aimed to see whether a change in the concentration-dependent contractions. Prazosin (0.3 mM) oestrogen to androgen ratio alters prostate contractility. Isolated attenuated the responses induced by noradrenaline and EFS in organ bath studies using prostates from aromatase knockout all mice (P%0.019, nZ5–7), while cocaine (10 mM) attenuated (ArKO) mice which were homozygous (ArKOK/K)and the responses evoked by tyramine (P!0.001, nZ6). There were heterozygous (ArKOC/K) for the disrupted aromatase cyp19 no genotype differences in EFS- and noradrenaline-induced gene and wild-type littermates (ArKOC/C) were conducted. responses (PR0.506, nZ10–13). Prostates from ArKOK/K The distribution of noradrenergic nerves was visualized using and ArKOC/K mice were more sensitive to tyramine than the sucrose–potassium phosphate–glyoxylic acid method. prostates from ArKOC/C mice (P!0.001, nZ11–13). Dense ArKOK/K mice had increased prostate weights compared adrenergic innervation of the prostate was similar in all mice. with ArKOC/C mice. Frequency–response curves to electrical These results suggest that although the absence of aromatase field stimulation (EFS; 0.5 ms pulse duration, 60 V,0.1–20 Hz) increases prostatic growth, this translates only to a subtle and yielded frequency-dependent contractions, while noradrenaline selective increase in contractility in mature mice.
    [Show full text]
  • Us 8530498 B1 3
    USOO853 0498B1 (12) UnitedO States Patent (10) Patent No.: US 8,530,498 B1 Zeldis (45) Date of Patent: *Sep. 10, 2013 (54) METHODS FORTREATING MULTIPLE 5,639,476 A 6/1997 OShlack et al. MYELOMAWITH 5,674,533 A 10, 1997 Santus et al. 3-(4-AMINO-1-OXO-1,3-DIHYDROISOINDOL- 395 A 22 N. 2-YL)PIPERIDINE-2,6-DIONE 5,731,325 A 3/1998 Andrulis, Jr. et al. 5,733,566 A 3, 1998 Lewis (71) Applicant: Celgene Corporation, Summit, NJ (US) 5,798.368 A 8, 1998 Muller et al. 5,874.448 A 2f1999 Muller et al. (72) Inventor: Jerome B. Zeldis, Princeton, NJ (US) 5,877,200 A 3, 1999 Muller 5,929,117 A 7/1999 Muller et al. 5,955,476 A 9, 1999 Muller et al. (73) Assignee: Celgene Corporation, Summit, NJ (US) 6,020,358 A 2/2000 Muller et al. - 6,071,948 A 6/2000 D'Amato (*) Notice: Subject to any disclaimer, the term of this 6,114,355 A 9, 2000 D'Amato patent is extended or adjusted under 35 SS f 1939. All et al. U.S.C. 154(b) by 0 days. 6,235,756 B1 5/2001 D'Amatoreen et al. This patent is Subject to a terminal dis- 6,281.230 B1 8/2001 Muller et al. claimer 6,316,471 B1 1 1/2001 Muller et al. 6,326,388 B1 12/2001 Man et al. 6,335,349 B1 1/2002 Muller et al. (21) Appl. No.: 13/858,708 6,380.239 B1 4/2002 Muller et al.
    [Show full text]
  • Identification of Chalcone Derivatives As Putative Non-Steroidal Aromatase
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Online Publishing @ NISCAIR Indian Journal of Chemistry Vol. 59B, February 2020, pp. 283-293 Identification of chalcone derivatives as putative non-steroidal aromatase inhibitors potentially useful against breast cancer by molecular docking and ADME prediction Umang Shah*a, Samir Patela, Mehul Patela, Karan Gandhia & Ashish Patelb a Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa 388 421, India b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Parul University, P.O. Limda 391 760, Dist. Vadodara, India E-mail: [email protected] Received 30 August 2019; accepted (revised) 16 October 2019 Aromatase is an influential target to overcome estrogen receptor positive breast cancer, as the enzyme is responsible for conversion of androstenedione to estrone, a promising drug target for therapeutic management of breast cancer. Chalcones are prominent biosynthetic compounds and parent candidate for the synthesis of heterocycles with diversified biological activities. The prime objective of the present study is to evaluate the binding interaction of 2-hydroxyphenyl- prop-2-en-1- one (1A-1X), 2-hydroxy-4-methoxyphenyl- prop-2-en-1-one (3A-3X), 2,4-dihydroxyphenyl- prop-2-en-1-one (9A-9X) and 1-hydroxynaphthalen-2-yl-prop-2-en-1-one (5A-5X) derivatives with aromatase enzyme by molecular docking study and also check their ADME properties by maestro suit. The designed chalcones derivatives have been docked against our target protein with PDB id 3S7S retrieved from the protein data bank, whereas exemestane has been taken as the positive control.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • 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.
    [Show full text]
  • WO 2017/112768 Al 29 June 2017 (29.06.2017) P O P C T
    (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 2017/112768 Al 29 June 2017 (29.06.2017) P O P C T (51) International Patent Classification: Delaware 19707 (US). ZHUANG, Linghang; 3135 Fox C07D 471/10 (2006.01) A61K 31/47 (2006.01) Drive, Chalfont, Pennsylvania 18914 (US). C07D 487/10 (2006.01) A61K 31/519 (2006.01) (74) Agents: DAVEY, PH.D., Evan A. et al; Fish & Richard C07D 495/04 (2006.01) A61P 35/02 (2006.01) son P.C., P.O. Box 1022, Minneapolis, Minnesota 55440- C07D 513/04 (2006.01) 1022 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 16/0680 16 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 1 December 2016 (21 .12.2016) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (26) Publication Language: English KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (30) Priority Data: NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, 62/270,973 22 December 201 5 (22. 12.2015) US RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (71) Applicant: VITAE PHARMACEUTICALS, INC.
    [Show full text]
  • Aromatase and Its Inhibitors: Significance for Breast Cancer Therapy † EVAN R
    Aromatase and Its Inhibitors: Significance for Breast Cancer Therapy † EVAN R. SIMPSON* AND MITCH DOWSETT *Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia; †Department of Biochemistry, Royal Marsden Hospital, London SW3 6JJ, United Kingdom ABSTRACT Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of aromatase inhibitors has found much less favor due to poor efficacy and unsustainable side effects. Now, however, the situation is changing rapidly with the introduction of the so-called phase III inhibitors, which display high affinity and specificity towards aromatase. These compounds have been tested in a number of clinical settings and, almost without exception, are proving to be more effective than tamoxifen. They are being approved as first-line therapy for elderly women with advanced disease. In the future, they may well be used not only to treat young, postmenopausal women with early-onset disease but also in the chemoprevention setting. However, since these compounds inhibit the catalytic activity of aromatase, in principle, they will inhibit estrogen biosynthesis in every tissue location of aromatase, leading to fears of bone loss and possibly loss of cognitive function in these younger women. The concept of tissue-specific inhibition of aromatase expression is made possible by the fact that, in postmenopausal women when the ovaries cease to produce estrogen, estrogen functions primarily as a local paracrine and intracrine factor. Furthermore, due to the unique organization of tissue-specific promoters, regulation in each tissue site of expression is controlled by a unique set of regulatory factors.
    [Show full text]
  • C19) United States 02) Patent Application Publication (10) Pub
    1111111111111111 IIIIII IIIII 111111111111111 111111111111111 IIIII IIIII IIIII 1111111111 11111111 US 20190241665Al c19) United States 02) Patent Application Publication (10) Pub. No.: US 2019/0241665 Al KREEGER et al. (43) Pub. Date: Aug. 8, 2019 (54) METHODS OF INHIBITING METASTASIS IN C07K 16/24 (2006.01) CANCER C12N 15/113 (2006.01) A61K 31/439 (2006.01) (71) Applicant: WISCONSIN ALUMNI RESEARCH (52) U.S. Cl. FOUNDATION, Madison, WI (US) CPC .......... C07K 1612854 (2013.01); A61P 35/04 (2018.01); C07K 16/24 (2013.01); Cl2N (72) Inventors: PAMELA KAY KREEGER, 2310/14 (2013.01); C12N 15/1138 (2013.01); MIDDLETON, WI (US); MOLLY A61K 31/439 (2013.01); C07K 2317/76 JANE CARROLL, MADISON, WI (2013.01); C07K 16/2866 (2013.01) (US); KAITLIN C. FOGG, FITCHBURG, WI (US) (57) ABSTRACT (21) Appl. No.: 16/256,065 As described herein, a method of inhibiting metastasis in (22) Filed: Jan. 24, 2019 cancer includes administering to a human subject diagnosed with a cancer of an organ of the peritoneal cavity a thera­ Related U.S. Application Data peutically effective amount of an inhibitor of CCR5 or P-selectin. Preferably the subject has a tumor positive for a (60) Provisional application No. 62/621,769, filed on Jan. ligand of P-selectin such as a CD24+ or PSGL-1 + tumor. 25, 2018. Analysis of samples from HGSOC patients confirmed increased MIP-1 fJ and P-selectin, suggesting that this novel Publication Classification multi-cellular mechanism can be targeted to slow or stop (51) Int. Cl. metastasis in cancers such as high-grade serous ovarian C07K 16/28 (2006.01) cancer, for example by using anti-CCR5 and P-selectin A61P 35/04 (2006.01) therapies developed for other indications.
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • INTERRELATIONSHIPS of the ESTROGEN-PRODUCING ENZYMES NETWORK in BREAST CANCER DISSERTATION Presented in Partial Fulfillment Of
    INTERRELATIONSHIPS OF THE ESTROGEN-PRODUCING ENZYMES NETWORK IN BREAST CANCER DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Wendy L. Rich, M.S. ∗∗∗∗∗ The Ohio State University 2009 Dissertation Committee: Approved by Pui-Kai Li, Ph.D., Adviser Robert W. Brueggemeier, Ph.D. Karl A. Werbovetz, Ph.D. Adviser Graduate Program in Pharmacy Charles L. Shapiro M.D. ABSTRACT In the United States, breast cancer is the most common non-skin malignancy and the second leading cause of cancer-related death in women. However, earlier detection and new, more effective treatments may be responsible for the decrease in overall death rates. Approximately 60% of breast tumors are estrogen receptor (ER) positive and thus their cellular growth is hormone-dependent. Elevated levels of estrogens, even in post- menopausal women, have been implicated in the development and progression of hormone-dependent breast cancer. Hormone therapies seek to inhibit local estrogen action and biosynthesis, which can be produced by pathways utilizing the enzymes aromatase or steroid sulfatase (STS). Cyclooxygenase-2 (COX-2), typically involved in inflammation processes, is a major regulator of aromatase expression in breast cancer cells. STS, COX-2, and aromatase are critical for estrogen biosynthesis and have been shown to be over-expressed in breast cancer. While there continues to be extensive study and successful design of potent aromatase inhibitors, much remains unclear about the regulation of STS and the clinical applications for its selective inhibition. Further studies exploring the relationships of STS with COX-2 and aromatase enzymes will aid in the understanding of its role in cancer cell growth and in the development of future hormone- dependent breast cancer therapies.
    [Show full text]
  • Delaying and Reversing Frailty: a Systematic Review of Primary Care Interventions
    Research John Travers, Roman Romero-Ortuno, Jade Bailey and Marie-Therese Cooney Delaying and reversing frailty: a systematic review of primary care interventions INTRODUCTION Abstract Frailty has been described as the most Frailty has long been in the lexicon of problematic expression of population ageing Background everyday language. ‘How easily the wind in the context of this considerable growth.3 It Recommendations for routine frailty screening overturns a frail tree’, Buddha reflected has forced fundamental changes in national in general practice are increasing as frailty 1 prevalence grows. In England, frailty identification some 2500 years ago. From such historic health policies. For example, since 2017 became a contractual requirement in 2017. prevalence has come an inherited instinct the new General Medical Services (GMS) However, there is little guidance on the most for recognising frailty. However, it is only contract in England mandates that all effective and practical interventions once frailty primary care practices use an appropriate has been identified. in recent years that frailty has come into focus for more rigorous medical definition tool to identify patients aged ≥65 years who Aim in a shift of emphasis from single-system are living with moderate or severe frailty. To assess the comparative effectiveness and ease of implementation of frailty interventions in conditions to unifying constructs for holistic For patients living with severe frailty, the primary care. patient care. practice must undertake a clinical review, Frailty can be described as a state of provide an annual medication review, Design and setting A systematic review of frailty interventions in physiological vulnerability with diminished discuss whether the patient has fallen in primary care.
    [Show full text]