Estrogens occurring naturally in the body are metabolized to
catecholestrogens (2- and 4-hydroxyestradiol) by the
cytochrome P450 enzymes. 2-Hydroxy
catecholestrogens are further metabolized by
catechol-O-methyltransferase to
2-methoxyestradiol, which is known to be protective against
tumor formation.
2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing
tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the
colchicine-binding site, have been reported. The exact mechanism of action of
2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing
tumor growth in a variety of cell lines.
2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for
estrogen receptor alpha compared with that of
estradiol, and its affinity for
estrogen receptor beta is even lower than that of
estrogen receptor alpha, thus it has minimal estrogenic activity.
2-Methoxyestradiol is distinct because of its inability to engage
estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of
estrogen receptors alpha and beta. A phase I clinical trial of
2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with
breast cancer showed significant reduction in bone
pain and
analgesic intake in some patients, with no significant adverse effects. Another phase I study of
2-methoxyestradiol 200-1,000 mg/day in combination with
docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic
breast cancer showed no serious
drug-related adverse effects. A phase II randomized, double-blind trial of
2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with
hormone-refractory
prostate cancer showed that it was well tolerated and showed
prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.