2-methoxyestradiol, a promising anticancer agent

Pharmacotherapy

Volumn 23, Issue 2, 2003, Pages 165-172

  Lakhani, Nehal J ^a   Sarkar, Mohamadi A ^a   Venitz, Jurgen ^a   Figg, William D ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 METHOXYESTRADIOL; ANALGESIC AGENT; CATECHOL ESTROGEN; CATECHOL METHYLTRANSFERASE; COLCHICINE; CYTOCHROME P450; DOCETAXEL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; LIVER ENZYME; PROSTATE SPECIFIC ANTIGEN;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BONE PAIN; BREAST CANCER; BREAST METASTASIS; CANCER CELL CULTURE; CANCER HORMONE THERAPY; CANCER INHIBITION; CELL GROWTH; CLINICAL TRIAL; DIARRHEA; DOSE RESPONSE; DRUG ACTIVITY; DRUG METABOLISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG TOLERABILITY; DRUG TRANSFORMATION; ESTROGEN METABOLISM; ESTROGEN THERAPY; FATIGUE; HAND FOOT SYNDROME; HEART PROTECTION; HOT FLUSH; HUMAN; LIVER DYSFUNCTION; LIVER FUNCTION; NONHUMAN; PROSTATE CANCER; REVIEW; SIDE EFFECT; SMOOTH MUSCLE FIBER; SOLID TUMOR; TOXICITY; TREATMENT OUTCOME; TUMOR CELL; VASCULAR SMOOTH MUSCLE;

ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; CLINICAL TRIALS, PHASE I; CLINICAL TRIALS, PHASE II; DOUBLE-BLIND METHOD; ESTRADIOL; FEMALE; HUMANS; MALE; PROSTATIC NEOPLASMS; RANDOMIZED CONTROLLED TRIALS;

EID: 0037320432     PISSN: 02770008     EISSN: None     Source Type: Journal    
DOI: 10.1592/phco.23.2.165.32088     Document Type: Review

References (61)

1. James VHT, Reed MJ, Lai LC, et al. Regulation of estrogen concentrations in human breast tissues. Ann NY Acad Sci 1990;595:227-35.
2. Malet C, Vacca A, Kuttnen F, Mauvais-Jarvis PJ. 17β-Estradiol dehydrogenase (E2DH) activity in T47D cells. J Steroid Biochem Mol Biol 1991;39:769-75.
3. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol 2001;45:S116-24.
4. Dubey RK, Gillespie DG, Zacharia LC, et al. Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms. Biochem Biophys Res Comm 2000;278:27-33.
5. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973;36:207-14.
6. MacDonald PC, Madden JD, Brenner PF, Wilson JD, Siiteri PK. Origin of estrogen in normal men and in women with testicular feminization. J Clin Endocrinol Metab 1979;49:905-16.
7. Shou M, Korzekwa K, Brooks EN, Krausz KW, Gonzalez FJ, Gelboin HV. Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis 1997;18:207-14.
8. Aoyama T, Korzekwa K, Nagata K, Gillete J, Gelboin HV, Gonzalez FJ. Estradiol metabolism by cDNA expressed human cytochrome P450s. Endocrinology 1990;126:3101-6.
9. Powell WA, Mitchell BF, Challis JR. Effect of steroids on progesterone output by explants of human chorion. Gynecol Obstet Invest 1986;22:64-72.
10. Kerlan V, Dreano Y, Bercovici JP, Beaune PH, Floch HH, Berthou F. Nature of cytochrome P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes. Biochem Pharmacol 1992;44:1745-6.
11. Ball P, Kunppen R. Formation, metabolism and physiologic importance of catecholestrogens. Am J Obstet Gynecol 1990;163:2163-70.
12. Schneider J, Huh MM, Bradlow HL, Fishman J. Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 1984;259:4840-5.
13. Vadlamuri SV, Glover DD, Turner T, Sarkar MA. Regiospecific distribution of CYP1A1 and CYP1B1 in human uterine tissue. Cancer Lett 1998;122:143-50.
14. Axelrod J, Tomchick R. Enzymatic o-methylation of epinephrine and other catechols. J Biol Chem 1958;233:702-5.
15. Campbell NRC, Dunnette JH, Mwaluko G, Van Loon J, Weinshilboum RM. Platelet phenol sulfotransferase and erythrocyte catechol-o-methyltransferase activities: correlation with methyldopa metabolism in man. Clin Pharmacol Ther 1984;35:55-63.
16. Liehr JG. Mechanism of metabolic activation and inactivation of catecholestrogens: a basis of genotoxicity. Polycyclic Aromat Compd 1994;6:229-39.
17. Liehr JG, Ulubelen AA, Strobel HW. Cytochrome P-450 mediated redox cycling of estrogens. J Biol Chem 1986;261:16865-70.
18. Liehr JG, Roy D. Free radical generation by redox cycling of estrogens. Free Radic Biol Med 1990;8:415-23.
19. Schneider J, Kinne D, Fracchia A, Pierce V, Bradlow HL, Fishman J. Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci USA 1982;79:3047-51.
20. Osborne MP, Karmali RA, Hershcopf RJ, et al. Omega-3 fatty acids: modulation of estrogen metabolism and potential for breast cancer prevention. Cancer Invest 1988;8:629-31.
21. Adlercreutz H, Fotsis T, Hockerstedt K, et al. Diet and urinary estrogen profile in premenopausal omnivorous and vegetarian women and in premenopausal women with breast cancer. J Steroid Biochem 1989;34:527-30.
22. Milewich L, Garcia RL, Gerrity LW. Steroid sulfatase and 17β-hydroxysteroid oxidoreductase activities in mouse tissues. J Steroid Biochem 1984;21:529-38.
23. Senafi SB, Clarke DJ, Burchell B. Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. Biochem J 1994;303:233-40.
24. Mojarrabi B, Butler R, Machenzie PI. cDNA cloning and characterization of the human UDP-glucuronosyltransferases, UGT1A3. Biochem Biophys Res Commun 1996;225:785-90.
25. Cheng Z, Rios GR, King CD, et al. Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3 and 2B7. Toxicol Sci 1998;45:52-7.
26. Zhu BT, Evaristus EN, Antoniak SK, Sarabia SF, Ricci MJ, Liehr JG. Metabolic deglucuronidation and demethylation of estrogen conjugates as a source of parent estrogens and catecholestrogen metabolites in Syrian hamster kidney, a target organ of estrogen induced tumorigenesis. Toxicol Appl Pharmacol 1996;136:186-93.
27. Schumacher G, Kataoka M, Roth JA, Mukhopadhyay T. Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. Clin Cancer Res 1999;5:493-9.
28. Fotsis T, Zhang Y, Pepper MS, et al. The endogenous oestrogen metabolite 2-methoxyestradiol inhibits angiogenesis and suppresses tumor growth. Nature 1994;368:237-9.
29. Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and Taxol. Cancer Res 1997;57:81-6.
30. LaValee TM, Zhan XH, Herbstritt CJ, Kough EC, Green SJ, Pribluda VS. 2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors α and β. Cancer Res 2002;62:3691-7.
31. Cushman M, He HM, Katzenellenbogen JA, Lin CM, Hamel E. Synthesis, antitubulin and antimitotic activity, and cytotoxicity of analogs of 2-methoxyestradiol, an endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine binding site. J Med Chem 1995;38:2041-9.
32. Mukhopadhyay T, Roth JA. Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene 1997;14:379-84.
33. Pribluda VS, Gubish ER Jr, Treston A, La Vallee TM, Swartz G, Green SJ. 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate. Cancer Metastasis Rev 2000;19:173-9.
34. Attalla H, Makela TP, Adlercreutz H, Anderson LC. 2-Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin. Biochem Biophys Res Commun 1996;228:467-73.
35. Seegers JC, Lottering ML, Grobler CJS, et al. The mammalian metabolite 2-methoxyestradiol affects p53 levels and apoptosis induction in transformed cells but not normal cells. J Steroid Biochem Molec Biol 1997;62:253-67.
36. Josefsson E, Tarkowski A. Suppression of type II collagen-induced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol. Arthritis Rheum 1997;40:154-63.
37. Aizu-Yakota E, Susaki A, Sato Y. Natural estrogens induce modulation of microtubules in Chinese hamster V79 cells in culture. Cancer Res 1995;55:1863-8.
38. Spicer LJ, Hammond JM. Catecholestrogens inhibit proliferation and DNA synthesis of porcine granulose cells in vitro: comparison with estradiol, 5-α-dihydrotestosterone, gonadotropins and catecholamines. Mol Cell Endocrinol 1989;64:119-26.
39. Nishigaki I, Sasaguri Y, Yagi K. Antiproliferative effect of 2-methoxyestradiol on cultured smooth muscle cells from rabbit aorta. Atherosclerosis 1995;113:167-70
40. Pico C, Puigserver P, Oliver P, Palou A. 2-methoxyestradiol, an endogenous metabolite of 17 β-estradiol, inhibits adipocyte proliferation. Mol Cell Biochem 1998;189:1-7.
41. Yue TL, Wang X, Louden CS, et al. 2-Methoxyestradiol, an endogenous estrogen metabolite induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress activated protein kinase signaling pathway and Fas expression. Mol Pharmacol 1997;51:951-62.
42. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
43. Hanahan D, Folkman J. Patterns and emerging mechanisms of angiogenic switch during tumorigenesis. Cell 1996;86:353-64.
44. Nicosia FR, Ottinetti A. Growth of microvessels in serum-free matrix cultures of rat aorta. Lab Invest 1990;63:115-21.
45. Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation which is species dependent. Biochem Pharmacol 1998;55:1827-34.
46. Wassberg E. Angiostatic treatment of neuroblastoma. Ups J Med Sci 1999;104:1-24.
47. Shang W, Konidari I, Schomberg DW. 2-Methoxyestradiol, an endogenous estradiol metabolite, differentially inhibits granulose and endothelial cell mitosis: a potent follicular antiangiogenic regulator. Biol Reprod 2001;65:622-7.
48. La Valee TM, Zhan XH, Herbstritt CJ, et al. 2-Methoxyestradiol induces apoptosis through activation of the extrinsic pathway [abstr]. Presented at the 93rd annual meeting of the American Association for Cancer Research, San Francisco, CA, April 6-10, 2002.
49. Kataoka M, Schumacher G, Cristiano RJ, Atkinson EN, Roth JA, Mukhopadhyay T. An agent that increases tumor suppressor transgene product coupled with systemic transgene delivery inhibits growth of metastatic lung cancer in vivo. Cancer Res 1998;58:4761-5.
50. Zacharia LC, Jackson EK, Gillespie DG, Dubey RK. Increased 2-methoxyestradiol production in human coronary versus aortic vascular cells. Hypertension 2001;37:658-62.
51. Purohit A, Singh A, Ghilchik MW, Reed MJ. Inhibition of tumor necrosis factor α stimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol. Biochem Biophys Res Commun 1999;261:214-17.
52. D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicines site. Proc Natl Acad Sci USA 1994;91:3964-8.
53. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 2000;407:390-5.
54. Kachadourian R, Liochev SI, Cabelli DE, Patel MN, Fridovich I, Day BJ. 2-Methoxyestradiol does not inhibit superoxide dismutase. Arch Biochem Biophys 2001;392:349-53.
55. lafrati MD, Karas RH, Aronovitz M, et al. Estrogen inhibits the vascular injury response in estrogen receptor α-deficient mice. Nat Med 1997;3:545-8.
56. Karas RH, Hodgin JB, Kwoun M, et al. Estrogen inhibits the vascular injury response in estrogen receptor β-deficient female mice. Proc Natl Acad Sci USA 1999;96:15133-6.
57. Barchiesi F, Jackson EK, Gillespie DG, Zacharia LC, Fingerle J, Dubey RK. Methoxyestradiols mediate estradiol-induced antimitogenesis in human aortic SMCs. Hypertension 2002;39:874-9.
58. EntreMed, Inc. Investigators brochure: 2-methoxyestradiol, initial investigational new drug application. Rockville, MD; 2000.
59. 2) in patients with refractory metastatic breast cancer [abstr]. Presented at the 37th annual meeting of the American Society of Clinical Oncology, San Francisco, May 12-15, 2001.
60. Wilding G, Sweeney C, King DM, et al. Phase 2, multicenter, randomized, double blind, safety, pharmacokinetic, pharmacodynamic and efficacy study of two doses of 2-methoxyestradiol administered orally in patients with hormone refractory prostate cancer [abstr]. Presented at the 38th annual meeting of the American Society of Clinical Oncology, Orlando, May 18-21, 2002.
61. 2) plus docetaxel in patients with metastatic breast cancer [abstr]. Presented at the 38th annual meeting of the American Society of Clinical Oncology, Orlando, May 18-21, 2002.