2-Methoxyestradiol

2-Methoxyestradiol (2-ME2, 2-MeO-E2) is a natural metabolite of estradiol and 2-hydroxyestradiol (2-OHE2). It is specifically the 2-methyl ether of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis), hence it is an angiogenesis inhibitor.<ref>Template:Cite journal</ref> It also acts as a vasodilator<ref>Template:Cite journal</ref> and induces apoptosis in some cancer cell lines.<ref>Template:Cite journal</ref> 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors (2,000-fold lower activational potency relative to estradiol).<ref>Template:Cite journal</ref> However, it retains activity as a high-affinity agonist of the G protein-coupled estrogen receptor (GPER) (10 nM, relative to 3–6 nM for estradiol).<ref name="pmid26023144">Template:Cite journal</ref><ref name="ThekkumkaraSnyder2016">Template:Cite book</ref> It can also be used to treat alveolar echinococcosis when combined with albendazole.

Clinical development

2-Methoxyestradiol was being developed as an experimental drug candidate with the tentative brand name Panzem.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It has undergone Phase 1 clinical trials against breast cancer.<ref>Template:Cite journal</ref> A phase II trial of 18 advanced ovarian cancer patients reported encouraging results in October 2007.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Preclinical models also suggest that 2-methoxyestradiol could also be effective against inflammatory diseases such as rheumatoid arthritis. Several studies have been conducted showing 2-methoxyestradiol is a microtubule inhibitor<ref>Template:Cite journal</ref> and is inhibitory against prostate cancer in rodents.<ref>Template:Cite journal</ref>

Template:As of, all clinical development of 2-methoxyestradiol has been suspended or discontinued.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This is significantly due to the very poor oral bioavailability of the molecule and also due to its extensive metabolism. Analogues have been developed in an attempt to overcome these problems.<ref name="pmid29618488">Template:Cite journal</ref> An example is 2-methoxyestradiol disulfamate (STX-140), the C3 and C17β disulfamate ester of 2-methoxyestradiol.<ref name="pmid29618488" />

Clinical effects

2-Methoxyestradiol was found to increase sex hormone-binding globulin (SHBG) levels in men by 2.5-fold at a dose of 400 mg/day and by 4-fold at a dose of 1,200 mg/day.<ref name="pmid16166441">Template:Cite journal</ref> Conversely, it did not seem to suppress testosterone levels.<ref name="pmid16166441" />

A study in 2000 indicated that 2-Methoxyestradiol induces G2/M cycle arrest, apoptosis and the disruption of thyroid follicles. This process results in the release of thyroid antigens that may play a role in high incidence of thyroid autoantibodies and autoimmune thyroid disease in women.<ref>Template:Cite journal</ref>

See also

• 2-Methoxyestriol
• 2-Methoxyestrone
• 4-Methoxyestradiol
• 4-Methoxyestrone
• MP-2001