INHIBITION OF PLACENTAL ESTRONE SULFATASE ACTIVITY AND MCF-7 BREAST-CANCER CELL-PROLIFERATION BY ESTRONE-3-AMINO DERIVATIVES

Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than in plasma, presumably due to in situ formation of estrogen. Several Lines of evidence indicate that the major source of estrogen in breast cancer cells may be from conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estr one sulfatase may thus be potential agents for the treatment of estrog en-dependent breast cancer. We designed and synthesized a series of es trone-3-amino derivatives as potential estrone sulfatase inhibitors. W e tested the inhibitory potential of these compounds using human place ntal microsomes, which contain a substantial amount of estrone sulfata se activity. Several compounds in the series significantly inhibited e strone sulfatase activity of the human placental microsomes when prese nt at 10 mu M. The IC50 for the estrone-3-amino compounds ranged from 8.7 to 14.6 mu M. We next tested the ability of the estrone-3-amino de rivatives to inhibit growth of the estrogen-dependent MCF-7 breast can cer cell line. MCF-7 cells showed substantial proliferation in the pre sence of 100 nM estrone sulfate in estrogen-free media, indicating tha t the cells were capable of converting estrone sulfate into estrone. T he proliferative effect of estrone sulfate (1 mu M) was significantly blocked by the estrone-3-amino derivatives at 10 mu M. The magnitude o f MCF-7 cell inhibition resulting from treatment with the estrone-3 am ino compounds was similar to or exceeded that of Danazol, but was less than the level resulting from treatment with estrone sulfamate. Using data from all of the compounds tested, inhibition of MCF-7 cell proli feration was positively correlated with inhibition of placental estron e sulfatase activity, suggesting that the reduction in cell growth was attributable to the blockade of sulfatase activity. In support of thi s, there was no relationship between inhibition of estrone sulfatase a ctivity and inhibition of cell growth when the estrogen-independent ce ll line MDA-MB-231 was used. Our results indicate the possible utility of estrone-3-amino derivatives for inhibition of estrone sulfatase ac tivity. Further, our data support the concept that estrone sulfatase i nhibitors may be useful as therapeutic agents for estrogen-dependent b reast cancers. Copyright (C) 1996 Elesevier Science Ltd.