Anti-breast cancer potential of SS5020, a novel benzopyran antiestrogen.
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.
Suzuki
Naomi
N
Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
Liu
Xiaoping
X
Laxmi
Y R Santosh
YR
Okamoto
Kanako
K
Kim
Hyo Jeong
HJ
Zhang
Guangxiang
G
Chen
John J
JJ
Okamoto
Yoshinori
Y
Shibutani
Shinya
S
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*
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
Calcif Tissue Int. 2003 Jun;72(6):710-6
14563000
J Clin Oncol. 1998 Jan;16(1):348-53
9440763
J Natl Cancer Inst. 1999 Oct 6;91(19):1654-62
10511593
Mutagenesis. 2009 Sep;24(5):391-404
19505894
Cancer Res. 2003 Dec 1;63(23):8461-5
14679010
Endocrinology. 1997 Sep;138(9):3901-11
9275080
J Natl Cancer Inst. 1991 Oct 16;83(20):1450-9
1920492
Obstet Gynecol Surv. 2008 Mar;63(3):163-81
18279543
Cancer Chemother Pharmacol. 1995;37(1-2):7-13
7497599
Chem Res Toxicol. 2006 Jun;19(6):852-8
16780365
Cancer Res. 1992 Mar 1;52(5):1360-3
1737398
JAMA. 2006 Jun 21;295(23):2742-51
16754728
Drug Metab Dispos. 2005 Nov;33(11):1673-8
16099924
Life Sci. 1983 Jun 20;32(25):2869-75
6406781
Cancer Res. 1999 May 1;59(9):2091-5
10232593
Clin Cancer Res. 2005 Jan 1;11(1):315-22
15671561
Chem Res Toxicol. 2002 Mar;15(3):305-11
11896676
Drugs Aging. 2007;24(5):361-79
17503894
N Engl J Med. 1998 Nov 26;339(22):1609-18
9828250
Drug Metab Rev. 2004 May;36(2):199-218
15237851
Carcinogenesis. 2000 Aug;21(8):1461-7
10910945
Cancer Res. 1993 Oct 1;53(19):4534-41
8402624
N Engl J Med. 2006 Jul 13;355(2):125-37
16837676
J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88
9747868
Drug Metab Dispos. 2006 Feb;34(2):311-7
16299164
Int J Cancer. 2010 Oct 1;127(7):1718-26
20073065
J Bone Miner Res. 1994 May;9(5):715-24
8053401
N Engl J Med. 1997 Dec 4;337(23):1641-7
9385122
Breast Cancer Res Treat. 2001 Jan;65(2):125-34
11261828
Cancer Res. 2002 Mar 1;62(5):1439-42
11888917
J Clin Oncol. 2007 Nov 1;25(31):4967-73
17971595
J Natl Cancer Inst. 1998 Oct 21;90(20):1552-8
9790548
Carcinogenesis. 1992 Dec;13(12):2197-203
1473224
Endocrinology. 1999 Dec;140(12):5828-40
10579349
Bioorg Med Chem Lett. 2004 Jul 5;14(13):3407-10
15177442
J Steroid Biochem. 1990 Jun 22;36(3):203-6
2142233
J Steroid Biochem. 1990 Jun 22;36(3):191-5
2142231
Carcinogenesis. 2001 Jun;22(6):839-49
11375888
Cancer Treat Rep. 1985 Feb;69(2):237-8
3971394
IARC Monogr Eval Carcinog Risks Hum. 1996;66:35-445
9132511
Arq Bras Endocrinol Metabol. 2006 Aug;50(4):720-34
17117297
Mayo Clin Womens Healthsource. 2008 Feb;12(2):3
18212675
Br J Cancer. 2005 Mar 28;92(6):1098-103
15756272
Am J Obstet Gynecol. 2002 Sep;187(3):521-7
12237621