Chemistry: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.[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] It can also be used to treat alveolar echinococcosis when combined with albendazole.
| Estrogen | ER RBA (%) | Uterine weight (%) | Uterotrophy | LH levels (%) | SHBG RBA (%) |
|---|---|---|---|---|---|
| Control | – | 100 | – | 100 | – |
| Estradiol | 100 | 506 ± 20 | +++ | 12–19 | 100 |
| Estrone | 11 ± 8 | 490 ± 22 | +++ | ? | 20 |
| Estriol | 10 ± 4 | 468 ± 30 | +++ | 8–18 | 3 |
| Estetrol | 0.5 ± 0.2 | ? | Inactive | ? | 1 |
| 17α-Estradiol | 4.2 ± 0.8 | ? | ? | ? | ? |
| 2-Hydroxyestradiol | 24 ± 7 | 285 ± 8 | +b | 31–61 | 28 |
| 2-Methoxyestradiol | 0.05 ± 0.04 | 101 | Inactive | ? | 130 |
| 4-Hydroxyestradiol | 45 ± 12 | ? | ? | ? | ? |
| 4-Methoxyestradiol | 1.3 ± 0.2 | 260 | ++ | ? | 9 |
| 4-Fluoroestradiola | 180 ± 43 | ? | +++ | ? | ? |
| 2-Hydroxyestrone | 1.9 ± 0.8 | 130 ± 9 | Inactive | 110–142 | 8 |
| 2-Methoxyestrone | 0.01 ± 0.00 | 103 ± 7 | Inactive | 95–100 | 120 |
| 4-Hydroxyestrone | 11 ± 4 | 351 | ++ | 21–50 | 35 |
| 4-Methoxyestrone | 0.13 ± 0.04 | 338 | ++ | 65–92 | 12 |
| 16α-Hydroxyestrone | 2.8 ± 1.0 | 552 ± 42 | +++ | 7–24 | <0.5 |
| 2-Hydroxyestriol | 0.9 ± 0.3 | 302 | +b | ? | ? |
| 2-Methoxyestriol | 0.01 ± 0.00 | ? | Inactive | ? | 4 |
| Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes: a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template. | |||||
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]
As of 2015[update], 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.[13]
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.[14]
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.[15]
See also
References
- ↑ "2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate". Cancer and Metastasis Reviews 19 (1–2): 173–179. 2000. doi:10.1023/a:1026543018478. PMID 11191057.
- ↑ "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. doi:10.1016/j.genm.2012.01.008. PMID 22366193.
- ↑ "2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway". Cancer Research 63 (2): 468–475. January 2003. PMID 12543804. http://cancerres.aacrjournals.org/content/63/2/468.long.
- ↑ "Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat". Endocrinology 144 (3): 785–792. March 2003. doi:10.1210/en.2002-220632. PMID 12586754.
- ↑ "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. doi:10.1124/pr.114.009712. PMID 26023144.
- ↑ "Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER)". Estrogen Receptors. Methods in Molecular Biology. 1366. Springer. 2016. pp. 11–7. doi:10.1007/978-1-4939-3127-9_2. ISBN 978-1-4939-3126-2.
- ↑ "EntreMed's Statistics". EntreMed, Inc.. http://www.entremed.com/go.cfm?do=Page.View&ID=31.
- ↑ "Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies". Clinical Cancer Research 15 (4): 1460–1465. February 2009. doi:10.1158/1078-0432.CCR-08-1599. PMID 19228747.
- ↑ "EntreMed Presents Results for Panzem NCD Phase 2 Ovarian Cancer Study". http://www.entremed.com/news/entremed-presents-results-for-panzem-ncd-phase-2-ovarian-cancer-study.
- ↑ "2-Methoxyestradiol, a promising anticancer agent". Pharmacotherapy 23 (2): 165–172. February 2003. doi:10.1592/phco.23.2.165.32088. PMID 12587805. https://zenodo.org/record/1236347.
- ↑ "Effects of hormone deprivation and 2-methoxyestradiol combination therapy on hormone-dependent prostate cancer in vivo". Neoplasia 7 (9): 838–846. September 2005. doi:10.1593/neo.05145. PMID 16229806.
- ↑ "2-Methoxyestradiol - CASI Pharmaceuticals". Adis Insight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800008361.
- ↑ 13.0 13.1 "SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects". Journal of Molecular Endocrinology 61 (2): T233–T252. August 2018. doi:10.1530/JME-18-0045. PMID 29618488.
- ↑ 14.0 14.1 "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. doi:10.1158/1078-0432.CCR-05-0440. PMID 16166441.
- ↑ "2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis". Molecular and Cellular Endocrinology 165 (1-2): 163–172. July 2000. doi:10.1016/S0303-7207(00)00249-5. PMID 10940494.
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