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 canter. A series of tricyclic coumarin sulfamates were synthesized, and the ir 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 6 67 COUMATE inhibited rat liver estrone sulfatase activity by 93%. 667 COUMA TE was devoid of estrogenicity, as indicated by its failure to stimulate th e growth of uteri in ovariectomized rats, In vivo, estrone sulfate-stimulat ed growth of uteri in ovariectomized rats was inhibited by 667 COUMATE. Usi ng the nitrosomethylurea-induced mammary tumor model, we found that 667 COU MATE caused regression of estrone sulfate-stimulated tumor growth in a dose -dependent manner. The identification of 667 COUMATE as a potent steroid su lfatase inhibitor will enable the therapeutic potential of this type of the rapy to be evaluated.