Few therapeutic treatment options are available for patients suffering from
metastatic androgen-independent prostate cancer. We investigated the abili
ty of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferati
on of a variety of human prostate cancer cell lines in vitro and to inhibit
the growth of androgen-independent prostate cancer in a transgenic mouse m
odel in vivo. Our results showed that 2-methoxyestradiol is a powerful grow
th inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cel
l flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked
accumulation of cells in the G2/M phase of the cell cycle and an increase
in the sub-GI fraction (apoptotic). In addition, staining for annexin V, ch
anges in nuclear morphology, and inhibition of caspase activity support a r
ole for apoptosis. More importantly, we showed that 2-methoxyestradiol inhi
bits prostate tumor progression in the G gamma /T-15 transgenic mouse model
of androgen-independent prostate cancer without toxic side effects. These
results in cell culture and an animal model support investigations into the
clinical use of 2-methoxyestradiol in patients with androgen-independent p
rostate cancer. (C) 2001 Academic Press.