title: Development of novel steroid sulfatase inhibitors; II. TZS-8478 potently inhibits the growth of breast tumors in postmenopausal breast cancer model rats.
abstract: In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.
authors.affiliation: Pharmacological Research Department, Teikoku Hormone Mfg. Co., Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki, Kanagawa 213-8522, Japan. saito-t1@kw.teikoku-hormone.co.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Saito
authors.forename: Setsuo
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Tomohito
authors.initials: T
authors.lastname: Fujii
authors.forename: Koji
authors.initials: K
authors.lastname: Bandoh
authors.forename: Saeko
authors.initials: S
authors.lastname: Fuse
authors.forename: Yukinao
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Koizumi
authors.forename: Toshi
authors.initials: T
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000097:blood; D005260:Female; D008099:Liver / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D017698:Postmenopause; D051381:Rats; D017207:Rats, Sprague-Dawley; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013451:Sulfonic Acids / Q000494:pharmacology*; D014599:Uterus / Q000201:enzymology
chemical_list: C487407:2',4'-dicyanobiphenyl-4-O-sulfamate; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D004967:Estrogens; D013451:Sulfonic Acids; D043266:Steryl-Sulfatase