2-Methoxyestradiol Explained

2-Methoxyestradiol should not be confused with 2-Methoxyestriol.

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.[1] It also acts as a vasodilator[2] and induces apoptosis in some cancer cell lines.[3] 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors (2,000-fold lower activational potency relative to estradiol).[4] 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).[5] [6]

Clinical development

2-Methoxyestradiol was being developed as an experimental drug candidate with the tentative brand name Panzem.[7] It has undergone Phase 1 clinical trials against breast cancer.[8] A phase II trial of 18 advanced ovarian cancer patients reported encouraging results in October 2007.[9]

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[10] and is inhibitory against prostate cancer in rodents.[11]

, all clinical development of 2-methoxyestradiol has been suspended or discontinued.[12] 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.[13] An example is 2-methoxyestradiol disulfamate (STX-140), the C3 and C17β disulfamate ester of 2-methoxyestradiol.

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.[14] Conversely, it did not seem to suppress testosterone levels.

See also

Notes and References

  1. Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ . 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate . Cancer and Metastasis Reviews . 19 . 1–2 . 173–179 . 2000 . 11191057 . 10.1023/a:1026543018478 . 20055299 .
  2. Koganti S, Snyder R, Thekkumkara T . Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells . Gender Medicine . 9 . 2 . 76–93 . April 2012 . 22366193 . 3322289 . 10.1016/j.genm.2012.01.008 .
  3. LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS . 6 . 2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway . Cancer Research . 63 . 2 . 468–475 . January 2003 . 12543804 .
  4. Sibonga JD, Lotinun S, Evans GL, Pribluda VS, Green SJ, Turner RT . Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat . Endocrinology . 144 . 3 . 785–792 . March 2003 . 12586754 . 10.1210/en.2002-220632 . free .
  5. Prossnitz ER, Arterburn JB . International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators . Pharmacological Reviews . 67 . 3 . 505–540 . July 2015 . 26023144 . 4485017 . 10.1124/pr.114.009712 .
  6. Book: Thekkumkara T, Snyder R, Karamyan VT . Estrogen Receptors . Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER) . Methods in Molecular Biology . 1366 . 11–7 . 2016 . Springer . 26585123 . 10.1007/978-1-4939-3127-9_2 . 978-1-4939-3126-2 .
  7. Web site: EntreMed's Statistics . EntreMed, Inc. . https://web.archive.org/web/20050504153826/http://www.entremed.com/go.cfm?do=Page.View&ID=31 . May 4, 2005 .
  8. Tevaarwerk AJ, Holen KD, Alberti DB, Sidor C, Arnott J, Quon C, Wilding G, Liu G . 6 . Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies . Clinical Cancer Research . 15 . 4 . 1460–1465 . February 2009 . 19228747 . 2892631 . 10.1158/1078-0432.CCR-08-1599 .
  9. Web site: EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study . dead . https://web.archive.org/web/20120717045228/http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study . July 17, 2012 .
  10. Lakhani NJ, Sarkar MA, Venitz J, Figg WD . 2-Methoxyestradiol, a promising anticancer agent . Pharmacotherapy . 23 . 2 . 165–172 . February 2003 . 12587805 . 10.1592/phco.23.2.165.32088 . 1541302 .
  11. Sato F, Fukuhara H, Basilion JP . Effects of hormone deprivation and 2-methoxyestradiol combination therapy on hormone-dependent prostate cancer in vivo . Neoplasia . 7 . 9 . 838–846 . September 2005 . 16229806 . 1501932 . 10.1593/neo.05145 .
  12. Web site: 2-Methoxyestradiol - CASI Pharmaceuticals. Adis Insight . Springer Nature Switzerland AG . 2 March 2017.
  13. Potter BV . SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects . Journal of Molecular Endocrinology . 61 . 2 . T233–T252 . August 2018 . 29618488 . 10.1530/JME-18-0045 . free .
  14. Sweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, Fife K, Armstrong V, Treston A, Sidor C, Wilding G . 6 . A phase II multicenter, randomized, double-blind, safety trial assessing the pharmacokinetics, pharmacodynamics, and efficacy of oral 2-methoxyestradiol capsules in hormone-refractory prostate cancer . Clinical Cancer Research . 11 . 18 . 6625–6633 . September 2005 . 16166441 . 10.1158/1078-0432.CCR-05-0440 . free .

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