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.
Purohit
A
A
Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College School of Medicine, St. Mary's Hospital, London, United Kingdom.
Woo
L W
LW
Potter
B V
BV
Reed
M J
MJ
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