title: Anti-breast cancer potential of SS5020, a novel benzopyran antiestrogen.
abstract: Treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. The carcinogenic effect is thought to involve initiation and/or promotion resulting from DNA damage induced by TAM as well as its estrogenic action. To minimize this serious side-effect while increasing the anti-breast cancer potential, a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020), was synthesized. Unlike TAM, SS5020 exhibits no genotoxic activity to damage DNA. Furthermore, SS5020 does not present significant uterotrophic potential in rats; in contrast, the structurally related compounds, TAM, toremifene, raloxifene (RAL) and SP500263 all have uterotrophic activity. At the human equivalent molar dose of TAM (0.33 or 1.0 mg/kg), SS5020 had much stronger antitumor potential than those same antiestrogens against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS5020. SS5020, lacking genotoxic and estrogenic actions, could be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer therapy and prevention.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Y R Santosh
authors.initials: YR
authors.lastname: Laxmi
authors.forename: Kanako
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Zhang
authors.forename: John J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D018736:DNA Adducts; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009360:Neoplastic Cells, Circulating; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000627:therapeutic use; D014468:Umbelliferones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: C555416:3-(4-((7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl)phenyl)acrylic acid; D002273:Carcinogens; D002934:Cinnamates; D018736:DNA Adducts; D020847:Estrogen Receptor Modulators; D014468:Umbelliferones; D013629:Tamoxifen; D015127:9,10-Dimethyl-1,2-benzanthracene
references.citation: Calcif Tissue Int. 2003 Jun;72(6):710-6
references.pmid: 14563000
references.citation: J Clin Oncol. 1998 Jan;16(1):348-53
references.pmid: 9440763
references.citation: J Natl Cancer Inst. 1999 Oct 6;91(19):1654-62
references.pmid: 10511593
references.citation: Mutagenesis. 2009 Sep;24(5):391-404
references.pmid: 19505894
references.citation: Cancer Res. 2003 Dec 1;63(23):8461-5
references.pmid: 14679010
references.citation: Endocrinology. 1997 Sep;138(9):3901-11
references.pmid: 9275080
references.citation: J Natl Cancer Inst. 1991 Oct 16;83(20):1450-9
references.pmid: 1920492
references.citation: Obstet Gynecol Surv. 2008 Mar;63(3):163-81
references.pmid: 18279543
references.citation: Cancer Chemother Pharmacol. 1995;37(1-2):7-13
references.pmid: 7497599
references.citation: Chem Res Toxicol. 2006 Jun;19(6):852-8
references.pmid: 16780365
references.citation: Cancer Res. 1992 Mar 1;52(5):1360-3
references.pmid: 1737398
references.citation: JAMA. 2006 Jun 21;295(23):2742-51
references.pmid: 16754728
references.citation: Drug Metab Dispos. 2005 Nov;33(11):1673-8
references.pmid: 16099924
references.citation: Life Sci. 1983 Jun 20;32(25):2869-75
references.pmid: 6406781
references.citation: Cancer Res. 1999 May 1;59(9):2091-5
references.pmid: 10232593
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):315-22
references.pmid: 15671561
references.citation: Chem Res Toxicol. 2002 Mar;15(3):305-11
references.pmid: 11896676
references.citation: Drugs Aging. 2007;24(5):361-79
references.pmid: 17503894
references.citation: N Engl J Med. 1998 Nov 26;339(22):1609-18
references.pmid: 9828250
references.citation: Drug Metab Rev. 2004 May;36(2):199-218
references.pmid: 15237851
references.citation: Carcinogenesis. 2000 Aug;21(8):1461-7
references.pmid: 10910945
references.citation: Cancer Res. 1993 Oct 1;53(19):4534-41
references.pmid: 8402624
references.citation: N Engl J Med. 2006 Jul 13;355(2):125-37
references.pmid: 16837676
references.citation: J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88
references.pmid: 9747868
references.citation: Drug Metab Dispos. 2006 Feb;34(2):311-7
references.pmid: 16299164
references.citation: Int J Cancer. 2010 Oct 1;127(7):1718-26
references.pmid: 20073065
references.citation: J Bone Miner Res. 1994 May;9(5):715-24
references.pmid: 8053401
references.citation: N Engl J Med. 1997 Dec 4;337(23):1641-7
references.pmid: 9385122
references.citation: Breast Cancer Res Treat. 2001 Jan;65(2):125-34
references.pmid: 11261828
references.citation: Cancer Res. 2002 Mar 1;62(5):1439-42
references.pmid: 11888917
references.citation: J Clin Oncol. 2007 Nov 1;25(31):4967-73
references.pmid: 17971595
references.citation: J Natl Cancer Inst. 1998 Oct 21;90(20):1552-8
references.pmid: 9790548
references.citation: Carcinogenesis. 1992 Dec;13(12):2197-203
references.pmid: 1473224
references.citation: Endocrinology. 1999 Dec;140(12):5828-40
references.pmid: 10579349
references.citation: Bioorg Med Chem Lett. 2004 Jul 5;14(13):3407-10
references.pmid: 15177442
references.citation: J Steroid Biochem. 1990 Jun 22;36(3):203-6
references.pmid: 2142233
references.citation: J Steroid Biochem. 1990 Jun 22;36(3):191-5
references.pmid: 2142231
references.citation: Carcinogenesis. 2001 Jun;22(6):839-49
references.pmid: 11375888
references.citation: Cancer Treat Rep. 1985 Feb;69(2):237-8
references.pmid: 3971394
references.citation: IARC Monogr Eval Carcinog Risks Hum. 1996;66:35-445
references.pmid: 9132511
references.citation: Arq Bras Endocrinol Metabol. 2006 Aug;50(4):720-34
references.pmid: 17117297
references.citation: Mayo Clin Womens Healthsource. 2008 Feb;12(2):3
references.pmid: 18212675
references.citation: Br J Cancer. 2005 Mar 28;92(6):1098-103
references.pmid: 15756272
references.citation: Am J Obstet Gynecol. 2002 Sep;187(3):521-7
references.pmid: 12237621