In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE.
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.
Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College School of Medicine, St. Mary's Hospital, London, United Kingdom.
A
A
Purohit
L W
LW
Woo
B V
BV
Potter
M J
MJ
Reed
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008770:Methylnitrosourea; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013429:Sulfatases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013451:Sulfonic Acids; D013997:Time Factors; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D003374:Coumarins; D013449:Sulfonamides; D013451:Sulfonic Acids; D004970:Estrone; C520511:irosustat; D008770:Methylnitrosourea; D013429:Sulfatases; C020121:estrone sulfatase; C017296:estrone sulfate