Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiol

Journal of Pharmaceutical Sciences

Volumn 96, Issue 7, 2007, Pages 1821-1831

  Lakhani, Nehal J ^a,b   Sparreboom, Alex ^a   Xu, Xia ^c   Veenstra, Timothy D ^c   Venitz, Jürgen ^b   Dahut, William L ^a   Figg, William D ^a,b  

^a NATIONAL CANCER INSTITUTE   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^c SAIC FREDERICK INC   (United States)

Author keywords

2 methoxyestradiol (2ME2); Enzyme kinetics; Metabolism

Indexed keywords

2 METHOXYESTRADIOL; DRUG METABOLITE; GLUCURONIC ACID; GLUCURONIDE;

ARTICLE; CASE REPORT; CONTROLLED STUDY; DRUG CONJUGATION; DRUG ELIMINATION; DRUG EXCRETION; DRUG METABOLISM; DRUG STRUCTURE; DRUG URINE LEVEL; ENZYME KINETICS; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; LIVER CLEARANCE; LIVER MICROSOME; MALE; MASS SPECTROMETRY; OVARY CANCER; PROSTATE CANCER; SULFATION;

EID: 34547204029     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.20837     Document Type: Article

References (33)

1. Guldberg HC, Marsden CA. 1975. Catechol-o-methyltransferase: Pharmacological aspects and physiological role. Pharmacol Rev 27:135-206.
2. Schneider J, Huh MM, Bradlow HL, Fishman J. 1984. Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 259:4840-4845.
3. Ball P, Knuppen R. 1990. Formation, metabolism, and physiologic importance of catecholestrogens. Am J Obstet Gynecol 163:2163-2170.
4. Liehr JG, Roy D. 1990. Free radical generation by redox cycling of estrogens. Free Radic Biol Med 8: 415-423.
5. Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG. 1997. Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 94: 10937-10942.
6. Shang W, Konidari I, Schomberg DW. 2001. 2-Methoxyestradiol, an endogenous estradiol metabolite, differentially inhibits granulosa and endothelial cell mitosis: A potential follicular antiangiogenic regulator. Biol Reprod 65:622-627.
7. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L. 1994. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237-239.
8. Schumacher G, Kataoka M, Roth JA, Mukhopadhyay T. 1999. Potent antitumor activity of 2-methoxyestradiol in human pancreatic cancer cell lines. Clin Cancer Res 5:493-499.
9. Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ. 1997. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 57:81-86.
10. Wassberg E. 1999. Angiostatic treatment of neuroblastoma. Ups J Med Sci 104:1-24.
11. Seegers JC, Lottering ML, Grobler CJ, van Papendorp DH, Habbersett RC, Shou Y, Lehnert BE. 1997. The mammalian metabolite, 2-methoxyestradiol, affects P53 levels and apoptosis induction in transformed cells but not in normal cells. J Steroid Biochem Mol Biol 62:253-267.
12. Zacharia LC, Jackson EK, Gillespie DG, Dubey RK. 2001. Increased 2-methoxyestradiol production in human coronary versus aortic vascular cells. Hypertension 37:658-662.
13. D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E. 1994. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 91:3964-3968.
14. Mabjeesh NJ, Escuin D, La Valee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P. 2003. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3:363-375.
15. Lakhani NJ, Sarkar MA, Venitz J, Figg WD. 2003. 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy 23:165-172.
16. Dahut WL, Lakhani N, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang X, Steinberg SM, Venitz J, Sparreboom A, Figg WD. 2006. Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and antiapoptotic agent, in patients with solid tumors. Cancer Biol Ther 5:22-27.
17. Kang MH, Figg WD, Ando Y, Blagosklonny MV, Liewehr D, Fojo T, Bates SE. 2001. The P-glycoprotein antagonist PSC 833 increases the plasma concentrations of 6alpha-hydroxypaclitaxel, a major metabolite of paclitaxel. Clin Cancer Res 7:1610-1617.
18. Rudek MA, Venitz J, Ando Y, Reed E, Pluda JM, Figg WD. 2003. Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: Clinical and experimental studies. J Clin Pharmacol 43:1124-1135.
19. Houston JB. 1994. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 47:1469-1479.
20. Lakhani N, Sparreboom A, Venitz J, Dahut WL, Figg WD. 2006. Plasma protein binding of the investigational anticancer agent, 2-methoxyestradiol. Anticancer Drugs 17:977-983.
21. Lakhani NJ, Lepper ER, Sparreboom A, Dahut WL, Venitz J, Figg WD. 2005. Determination of 2-methoxyestradiol in human plasma, using liquid chromatography-tandem mass spectrometry. Rapid Comm Mass Spec 19:1176-1182.
22. Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K. 2000. Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod 15: 1028-1036.
23. Powell WA, Mitchell BF, Chalks JR. 1986. Effects of steroids on progesterone output by explants of human chorion. Gynecol Obstet Invest 22:64-72.
24. Aoyama T, Korzekwa K, Nagata K, Gillette J, Gelboin HV, Gonzalez FJ. 1990. Estradiol metabolism by complementary deoxyribonucleic acid-expressed human cytochrome P450s. Endocrinology 126:3101-3106.
25. Shou M, Korzekwa KR, Brooks EN, Krausz KW, Gonzalez FJ, Gelboin HV. 1997. Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis 18:207-214.
26. Kerlan V, Dreano Y, Bercovici JP, Beaune PH, Floch HH, Berthou F. 1992. Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes. Biochem Pharmacol 44:1745-1756.
27. Senafi SB, Clarke DJ, Burchell B. 1994. Investigation of the substrate specificity of a cloned expressed human bilirubin UDP-glucuronosyltransferase: UDP-sugar specificity and involvement in steroid and xenobiotic glucuronidation. Biochem J 303:233-240.
28. Mojarrabi B, Butler R, Mackenzie PI. 1996. cDNA cloning and characterization of the human UDP glucuronosyltransferase, UGT1A3. Biochem Biophys Res Commun 225:785-790.
29. Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. 2000. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos 28:560-566.
30. Pacifici GM, Back DJ. 1988. Sulphation and glucuronidation of ethinyloestradiol in human liver in vitro. J Steroid Biochem 31:345-349.
31. Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, Santner SJ, Tekmal R, Demers L, Pauley R, Naftolin F, Mor G, Berstein L. 2000. Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr 27:95-112.
32. Hernandez JS, Watson RW, Wood TC, Weinshilboum RM. 1992. Sulfation of estrone and 17 beta-estradiol in human liver. Catalysis by thermostable phenol sulfotransferase and by dehydroepiandrosterone sulfotransferase. Drug Metab Dispos 20:413-422.
33. Raftogianis R, Creveling C, Weinshilboum R, Weisz J. 2000. Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr 27:113-124.