title: Anti-breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions.
abstract: Long-term treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. Several antiestrogens developed in last decades have been discontinued from clinical testing because of their undesirable effects on the uterus. To avoid such serious side-effect while increasing the drug's anti-breast cancer potential, new triphenylethylene antiestrogens, 2E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and 2E-3-{4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenyl}acrylic acid (SS1010), were designed as safer alternatives. Unlike TAM, SS1020 does not present significant uterotrophic potential in rats; in contrast, SS1010, a compound removing a 4-OH moiety from SS1020, represented weak uterotrophic activity. The structurally related compounds 4-hydroxytamoxifen, toremifene, ospemifene, raloxifene (RAL) and GW5638 all have uterotrophic activity. In addition, SS1020 and SS1010 exhibit no genotoxic activity to damage hepatic DNA in rats. Therefore, SS1020 was selected as a safer antiestrogen candidate and used for evaluating the antitumor potential in animals. At the human equivalent doses of TAM, SS1020 had antitumor potential much higher than that of TAM, RAL and GW5638 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 SS1020. SS1020, lacking estrogenic and genotoxic actions and having strong antitumor potency superior to that of TAM and RAL, could be a safer alternative for breast cancer therapy and prevention.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
authors.forename: Y R Santosh
authors.initials: YR
authors.lastname: Laxmi
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Kim
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; D000818:Animals; D018736:DNA Adducts / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000517:prevention & control*; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000627:therapeutic use; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D018736:DNA Adducts; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; D015127:9,10-Dimethyl-1,2-benzanthracene