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The development of potent steroid sulfatase inhibitors is an important new therapeutic strategy for the treatment of postmenopausal women with breast cancer. A series of tricyclic coumarin sulfamates were synthesized, and their inhibitory properties were examined in vitro and in vivo. In a placental microsomal assay system, 667 COUMATE emerged as the most potent inhibitor with an IC50 of 8 nM. Administration of a single dose (10 mg/kg, p.o.) of 667 COUMATE inhibited rat liver estrone sulfatase activity by 93%. 667 COUMATE was devoid of estrogenicity, as indicated by its failure to stimulate the growth of uteri in ovariectomized rats. In vivo, estrone sulfate-stimulated growth of uteri in ovariectomized rats was inhibited by 667 COUMATE. Using the nitrosomethylurea-induced mammary tumor model, we found that 667 COUMATE caused regression of estrone sulfate-stimulated tumor growth in a dose-dependent manner. The identification of 667 COUMATE as a potent steroid sulfatase inhibitor will enable the therapeutic potential of this type of therapy to be evaluated.

Type

Journal article

Journal

Cancer Res

Publication Date

01/07/2000

Volume

60

Pages

3394 - 3396

Keywords

Animals, Antineoplastic Agents, Cell Division, Coumarins, Estrone, Female, Humans, Liver, Mammary Neoplasms, Experimental, Methylnitrosourea, Ovariectomy, Rats, Rats, Inbred Strains, Structure-Activity Relationship, Sulfatases, Sulfonamides, Sulfonic Acids, Time Factors, Uterus