New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Steroids

Volumn 72, Issue 13, 2007, Pages 829-842

  Jordan, V Craig ^a  

^a FOX CHASE CANCER CENTER   (United States)

Author keywords

Arzoxifene; Ospemifene; Raloxifene; Selective estrogen receptor modulators; Selective serotonin reuptake inhibitors

Indexed keywords

4 HYDROXYNORTAMOXIFEN; ARZOXIFENE; CITALOPRAM; CYTOCHROME P450 2D6; FLUOXETINE; LASOFOXIFENE; OSPEMIFENE; PAROXETINE; RALOXIFENE; SERTRALINE; TAMOXIFEN; TAMOXIFEN CITRATE; UNCLASSIFIED DRUG; VENLAFAXINE;

ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER PREVENTION; CANCER RISK; CARCINOGENESIS; CLINICAL TRIAL; DRUG MECHANISM; DRUG METABOLISM; HUMAN; NONHUMAN; REVIEW;

ANTINEOPLASTIC AGENTS, HORMONAL; BREAST NEOPLASMS; FEMALE; HUMANS; MOLECULAR MIMICRY; SELECTIVE ESTROGEN RECEPTOR MODULATORS; TAMOXIFEN;

EID: 34548638977     PISSN: 0039128X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.steroids.2007.07.009     Document Type: Review

References (155)

1. Snyder K.R., Sparano N., and Malinowski J.M. Raloxifene hydrochloride. Am J Health Syst Pharm 57 18 (2000) 1669-1675 quiz 1676-1678
2. Jordan V.C. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2 (2003) 205-213
3. Harper M.J., and Walpole A.L. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 212 57 (1966) 87
4. Harper M.J., and Walpole A.L. Mode of action of I.C.I. 46,474 in preventing implantation in rats. J Endocrinol 37 1 (1967) 83-92
5. Harper M.J., and Walpole A.L. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 13 (1967) 101-119
6. Klopper A., and Hall M. New synthetic agent for the induction of ovulation. Preliminary trial in women. Br Med J 1 (1971) 152-154
7. Williamson J.G., and Ellis J.P. The induction of ovulation by tamoxifen. J Obstet Gynaecol Br Commonw 80 (1973) 844-847
8. Kennedy B.J. Hormone therapy for advanced breast cancer. Cancer 18 (1965) 1551-1557
9. Cole M.P., Jones C.T., and Todd I.D. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474. Br J Cancer 25 (1971) 270-275
10. Ward H.W. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1 844 (1973) 13-14
11. Jensen E.V., and Jacobson H.I. Basic guides to the mechanism of estrogen action. Recent Progr Hormone Res 18 (1962) 387-414
12. Jensen E.V., Block G.E., Smith S., Kyser K., and DeSombre E.R. Estrogen receptors and breast cancer response to adrenalectomy. Natl Cancer Inst Monogr 34 (1971) 55-70
13. Kiang D.T., and Kennedy B.J. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med 87 6 (1977) 687-690
14. Jensen E.V., and Jordan V.C. The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research. Clin Cancer Res 9 (2003) 1980-1989
15. Jordan V.C., and Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer 11 (1975) 205-206
16. Jordan V.C., and Dowse L.J. Tamoxifen as an anti-tumour agent: effect on oestrogen binding. J Endocrinol 68 02 (1976) 297-303
17. Jordan V.C., and Jaspan T. Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol 68 (1976) 453-460
18. Jordan V.C. Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy. Rev Endocr Relat Cancer Suppl (1978) 49-55
19. Jordan V.C., Dix C.J., and Allen K.E. The effectiveness of long term tamoxifen treatment in a laboratory model for adjuvant hormone therapy of breast cancer. Adjuvant Ther. Cancer 2 (1979) 19-26
20. Jordan V.C., and Allen K.E. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16 (1980) 239-251
21. Jordan V.C. Antitumour activity of the antioestrogen ICI 46,474 (tamoxifen) in the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem 5 (1974) 354
22. Jordan V.C. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinoma. Eur J Cancer 12 (1976) 419-424
23. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 354 (1998) 1451-1467
24. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (2005) 1687-1717
25. Jordan V.C., and Brodie A.M.H. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids 72 (2007) 7-25
26. Howell A., Cuzick J., Baum M., Buzdar A., Dowsett M., Forbes J.F., et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (2005) 60-62
27. Thurlimann B., Keshaviah A., Coates A.S., Mouridsen H., Mauriac L., Forbes J.F., et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (2005) 2747-2757
28. Goss P.E., Ingle J.N., Marino S., Robert N.J., Muss H.B., Piccart M.J., et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349 (2003) 1-10
29. Coombes R.C., Hall E., Gibson L.J., Paridaens R., Jassem J., Delozier T., et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350 11 (2004) 1081-1092
30. Jordan V.C. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 7 (2007) 46-53
31. Andersson T., Flockhart D.A., Goldstein D.B., Huang S.M., Kroetz D.L., Milos P.M., et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 78 (2005) 559-581
32. Jordan V.C., Collins M.M., Rowsby L., and Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75 2 (1977) 305-316
33. Allen K.E., Clark E.R., and Jordan V.C. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol 71 1 (1980) 83-91
34. Borgna J.L., and Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem 256 2 (1981) 859-868
35. Lien E.A., Solheim E., Kvinnsland S., and Ueland P.M. Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile. Cancer Res 48 8 (1988) 2304-2308
36. Lien E.A., Solheim E., Lea O.A., Lundgren S., Kvinnsland S., and Ueland P.M. Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49 8 (1989) 2175-2183
37. Johnson M.D., Zuo H., Lee K.H., Trebley J.P., Rae J.M., Weatherman R.V., et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85 2 (2004) 151-159
38. Desta Z., Ward B.A., Soukhova N.V., and Flockhart D.A. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310 3 (2004) 1062-1075
39. Crewe H.K., Lennard M.S., Tucker G.T., Woods F.R., and Haddock R.E. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 34 3 (1992) 262-265
40. Fromson J.M., Pearson S., and Bramah S. The metabolism of tamoxifen (I.C.I. 46,474). I. In laboratory animals. Xenobiotica 3 11 (1973) 693-709
41. Fromson J.M., Pearson S., and Bramah S. The metabolism of tamoxifen (ICI 46,474). Part II. In female patients. Xenobiotica 3 (1973) 711-713
42. Lieberman M.E., Jordan V.C., Fritsch M., Santos M.A., and Gorski J. Direct and reversible inhibition of estradiol-stimulated prolactin synthesis by antiestrogens in vitro. J Biol Chem 258 8 (1983) 4734-4740
43. Adam H.K., Gay M.A., and Moore R.H. Measurement of tamoxifen in serum by thin layer densitometry. J Endocrinol 84 (1980) 35-41
44. Adam H.K., Douglas E.J., and Kemp J.V. The metabolism of tamoxifen in humans. Biochem Pharmacol 27 (1979) 145-147
45. Kemp J.V., Adam H.K., Wakeling A.E., and Slater R. Identification and biological activity of tamoxifen metabolites in human serum. Biochem Pharmacol 32 (1983) 2045-2052
46. Bain R.R., and Jordan V.C. Identification of a new metabolite of tamoxifen in patient serum during breast cancer therapy. Biochem Pharmacol 32 2 (1983) 373-375
47. Jordan V.C., Bain R.R., Brown R.R., Brown R.R., Gosden B., and Santos M.A. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient during therapy for advanced breast cancer. Cancer Res 43 (1983) 1446-1450
48. Robinson S.P., Langan-Fahey S.M., and Jordan V.C. Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. Eur J Cancer Clin Oncol 25 12 (1989) 1769-1776
49. Jordan V.C., and Gosden B. Importance of the alkylamino-ethoxy side chain for the estrogenic and antiestrogenic actions of tamoxifen and trioxifene in the immature rat uterus. Mol Cell Endocrinol 27 (1982) 291-306
50. Lieberman M.E., Gorski J., and Jordan V.C. An estrogen receptor model to describe the regulation of prolactin synthesis by antiestrogens in vitro. J Biol Chem 258 8 (1983) 4741-4745
51. Katzenellenbogen J.A., Carlson K.E., and Katzenellenbogen B.S. Facile geometric isomerization of phenolic nonsteroidal estrogens and antiestrogens: limitations to the interpretation of experiments characterizing the activity of individual isomers. J Steroid Biochem 22 (1985) 589-596
52. Katzenellenbogen B.S., Norman M.J., Eckert R.L., Peltz S.W., and Mangel W.F. Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res 44 1 (1984) 112-119
53. Berthois Y., Katzenellenbogen J.A., and Katzenellenbogen B.S. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci USA 83 8 (1986) 2496-2500
54. Murphy C.S., Meisner L.F., Wu S.Q., and Jordan V.C. Short- and long-term estrogen deprivation of T47D human breast cancer cells in culture. Eur J Cancer Clin Oncol 25 12 (1989) 1777-1788
55. Jordan V.C., Lieberman M.E., Cormier E., Koch R., Bagley J.R., and Ruenitz P.C. Structural requirements for the pharmacological activity of nonsteroidal antiestrogens in vitro. Mol Pharmacol 26 2 (1984) 272-278
56. Jordan V.C., Koch R., Mittal S., and Schneider M.R. Oestrogenic and antioestrogenic actions in a series of triphenylbut-1-enes: modulation of prolactin synthesis in vitro. Br J Pharmacol 87 (1986) 217-223
57. Murphy C.S., Langan-Fahey S.M., McCague R., and Jordan V.C. Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitro. Mol Pharmacol 38 5 (1990) 737-743
58. Murphy C.S., Parker C.J., McCague R., and Jordan V.C. Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity. Mol Pharmacol 39 3 (1991) 421-428
59. Shiau A.K., Barstad D., Loria P.M., Cheng L., Kushner P.J., Agard D.A., et al. The structural basis of estrogen receptor/co-activator recognition and the antagonism of this interaction by tamoxifen. Cell 95 (1998) 927-937
60. Brzozowski A.M., Pike A.C., Dauter Z., Hubbard R.E., Bonn T., Engstrom O., et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389 6652 (1997) 753-758
61. Wolf D.M., and Jordan V.C. The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat 31 1 (1994) 129-138
62. Wolf D.M., and Jordan V.C. Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Res Treat 31 1 (1994) 117-127
63. MacGregor-Shafer J.I., Liu H., Bentrem D., Zapf J., and Jordan V.C. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex by substituting glycine for aspartate at amino acid 351. Cancer Res 60 (2000) 5097-5105
64. Levenson A.S., and Jordan V.C. The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor. Cancer Res 58 9 (1998) 1872-1875
65. Liu H., Lee E.-S., De Los Reyes A., Zapf J.W., and Jordan V.C. Silencing and reactivation of the selective estrogen receptor modulator (SERM)-ER alpha complex. Cancer Res 61 (2001) 3632-3639
66. Onate S.A., Tsai S.Y., Tsai M.J., and O'Malley B.W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270 5240 (1995) 1354-1357
67. Jordan VC, O'Malley BM. Selective estrogen receptor modulators and antihormonal resistance in breast cancer. J Clin Oncol; in press.
68. Jordan V.C., Gapstur S., and Morrow M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst 93 19 (2001) 1449-1457
69. Greaves P., Goonetilleke R., Nunn G., Topham J., and Orton T. Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res 53 17 (1993) 3919-3924
70. Hard G.C., Iatropoulos M.J., Jordan K., Radi L., Kaltenberg O.P., Imondi A.R., et al. Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. Cancer Res 53 19 (1993) 4534-4541
71. Fornander T., Rutqvist L.E., Cedermark B., Glas U., Mattsson A., Silfversward C., et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1 8630 (1989) 117-120
72. Fisher B., Costantino J.P., Redmond C.K., Fisher E.R., Wickerham D.L., and Cronin W.M. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86 7 (1994) 527-537 [see comments]
73. Han X.L., and Liehr J.G. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 52 (1992) 1360-1363
74. Rutqvist L.E., Johansson H., Signomklao T., Johansson U., Fornander T., and Wilking N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 87 (1995) 645-651
75. Styles J.A., Davies A., Lim C.K., De Matteis F., Stanley L.A., White I.N., et al. Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis 15 1 (1994) 5-9
76. Lim C.K., Zhi-Xin Y., Lamb J.H., Whihte I.N.H., DeMatteis F., and Smith L.L. A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis 15 (1994) 589-593
77. Moorthy B., Sriram P., Pathak D.N., Bodell W.J., and Randerath K. Tamoxifen metabolic activation: comparison of DNA adducts formed by microsomal and chemical activation of tamoxifen and 4-hydroxytamoxifen with DNA adducts formed in vivo. Cancer Res 56 1 (1996) 53-57
78. Pongracz K., Pathak D.N., Nakamura T., Burlingame A.L., and Bodell W.J. Activation of the tamoxifen derivative metabolite E to form DNA adducts: comparison with the adducts formed by microsomal activation of tamoxifen. Cancer Res 55 14 (1995) 3012-3015
79. Potter G.A., McCague R., and Jarman M. A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis 15 3 (1994) 439-442
80. Phillips D.H., Carmichael P.L., Hewer A., Cole K.J., and Poon G.K. Alpha-hydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNA-binding activity in rat hepatocytes. Cancer Res 54 21 (1994) 5518-5522
81. Phillips D.H., Potter G.A., Horton M.N., Hewer A., Crofton-Sleigh C., Jarman M., et al. Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates alpha-hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. Carcinogenesis 15 8 (1994) 1487-1492
82. Osborne M.R., Hewer A., Hardcastle I.R., Carmichael P.L., and Phillips D.H. Identification of the major tamoxifen-deoxyguanosine adduct formed in the liver DNA of rats treated with tamoxifen. Cancer Res 56 1 (1996) 66-71
83. Phillips D.H., Carmichael P.L., Hewer A., Cole K.J., Hardcastle I.R., Poon G.K., et al. Activation of tamoxifen and its metabolite alpha-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes. Carcinogenesis 17 1 (1996) 89-94
84. Osborne M.R., Hewer A., and Phillips D.H. Resolution of alpha-hydroxytamoxifen; R-isomer forms more DNA adducts in rat liver cells. Chem Res Toxicol 14 7 (2001) 888-893
85. Osborne M.R., Hewer A., and Phillips D.H. Stereoselective metabolic activation of alpha-hydroxy-N-desmethyltamoxifen: the R-isomer forms more DNA adducts in rat liver cells. Chem Res Toxicol 17 5 (2004) 697-701
86. Phillips D.H. Understanding the genotoxicity of tamoxifen?. Carcinogenesis 22 6 (2001) 839-849
87. Jordan V.C. What if tamoxifen (ICI 46,474) had been found to produce rat liver tumors in 1973? A personal perspective. Ann Oncol 6 1 (1995) 29-34
88. Mallory F.B., Wood C.S., and Gordon J.T. Photochemistry of stilbenes III. Some aspects of photocylisation to phenanthrenes. J Am Chem Soc 86 (1986) 3094-3102
89. Mendenhall L.W., Kobayashi H., Shih F.M.L., Sternson L.A., Higuchi T., and Fabian C. Clinical analysis of tamoxifen, an antineoplastic agent, in plasma. Clin Chem 24 (1978) 1518-1524
90. Golander Y., and Sternson L.A. Paired-ion chromatographis analysis of tamoxifen and two major metabolites in plasma. J Chromatogr 181 (1980) 41-49
91. Brown R.R., Bain R., and Jordan V.C. Determination of tamoxifen and metabolites in human serum by high-performance liquid chromatography with post-column fluorescence activation. J Chromatogr 272 2 (1983) 351-358
92. Camaggi C.M., Strocchi E., and Canova N. High performance liquid chromatographic analysis or tamoxifen and major metabolites in human plasma. J Chromatogr 275 (1983) 436-442
93. Lien E.A., Solheim E., and Ueland P.M. Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51 (1991) 4837-4844
94. Lee K.H., Ward B.A., Desta Z., Flockhart D.A., and Jones D.R. Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci 791 (2003) 245-253
95. Fried K.M., and Wainer I.W. Direct determination of tamoxifen and its four major metabolites in plasma using coupled column high-performance liquid chromatography. J Chromatogr B Biomed Appl 655 2 (1994) 261-268
96. Kikuta C., and Schmid R. Specific high-performance liquid chromatographic analysis of tamoxifen and its major metabolites by "on-line" extraction and post-column photochemical reaction. J Pharm Biomed Anal 7 3 (1989) 329-337
97. Stearns V., Johnson M.D., Rae J.M., Morocho A., Novielli A., Bhargava P., et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95 23 (2003) 1758-1764
98. Fabian C., Sternson L., and Barnett M. Clinical pharmacology of tamoxifen in patients with breast cancer: comparison of traditional and loading dose schedules. Cancer Treat Rep 64 6-7 (1980) 765-773
99. Patterson J.S., Settatree R.S., Adam H.K., and Kemp J.V. Serum concentrations of tamoxifen and major metabolite during long-term Nolvadex therapy, correlated with clinical response. Eur J Cancer Suppl 1 (1980) 89-92
100. Wilkinson P.M., Ribiero G.G., Adama H.K., Kemp J.V., and Patterson J.S. Tamoxifen (Nolvadex) therapy-rationale for loading dose followed by maintenance dose for patients with metastatic breast cancer. Cancer Chemother Pharmacol 10 (1982) 33-35
101. Jordan V.C. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest 6 5 (1988) 589-595
102. Lerner L.J., and Jordan V.C. The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res 50 (1990) 4177-4189
103. Jordan V.C. Selective estrogen receptor modulation: a personal perspective. Cancer Res 61 (2001) 5683-5687
104. Jordan V.C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem 46 7 (2003) 1081-1111
105. Ariazi E.A., Ariazi J.L., Cordera F., and Jordan V.C. Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem 6 (2006) 195-216
106. Buzdar A., Marcus C., Holmes F., Hug V., and Hortobagyi G. Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology 45 5 (1988) 344-345
107. Kemp D.C., Fan P.W., and Stevens J.C. Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metab Dispos 30 (2002) 694-700
108. Jeong E.J., Liu Y., Lin H., and Hu M. Species- and disposition model-dependent metabolism of raloxifene in gut and liver: role of UGT1A10. Drug Metab Dispos 33 (2005) 785-794
109. Suh N., Lamph W.W., Glasebrook A.L., Grese T.A., Palkowitz A.D., Williams C.R., et al. Prevention and treatment of experimental breast cancer with the combination of a new selective estrogen receptor modulator, arzoxifene, and a new rexinoid, LG 100268. Clin Cancer Res 8 10 (2002) 3270-3275
110. Baselga J., Llombart-Cussac A., Bellet M., Guillem-Porta V., Enas N., Krejcy K., et al. Randomized, double-blind multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients. Ann Oncol 14 (2003) 1383-1390
111. Buzdar A., O'Shaughnessy J.A., Booser D.J., Pippen Jr. J.E., Jones S.E., Munster P.N., et al. Phase II, randomized double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer. J Clin Oncol 21 (2003) 1007-1014
112. Falany J.L., Pilloff D.E., Leyh T.S., and Falany C.N. Sulfation of raloxifene and 4-hydroxytamoxifen by human cytosolic sulfotransferases. Drug Metab Dispos 34 (2006) 361-368
113. Rosati R.L., Da Silva Jardine P., Cameron K.O., Thompson D.D., Ke H.Z., Toler S.M., et al. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem 41 16 (1998) 2928-2931
114. Ke H.Z., Paralkar V.M., Grasser W.A., Crawford D.T., Qi H., Simmons H.A., et al. Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology 139 4 (1998) 2068-2076
115. Ke H.Z., Qi H., Crawford D.T., Chidsey-Frink K.L., Simmons H.A., and Thompson D.D. Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat. Endocrinology 141 4 (2000) 1338-1344
116. Tatee T., Carlson K.E., Katzenellenbogen J.A., Robertson D.W., and Katzenellenbogen B.S. Antiestrogens and antiestrogen metabolites: preparation of tritium-labeled (+/-)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxyl]-1.2-propanediol (U-23469) and characterization and synthesis of a biologically important metabolite. J Med Chem 22 12 (1979) 1509-1517
117. Legha S.S., Slavik M., and Carter S.K. Nafoxidine-an antiestrogen for the treatment of breast cancer. Cancer 38 4 (1976) 1535-1541
118. Cohen L.A., Pittman B., Wang C.X., Aliaga C., Yu L., and Moyer J.D. Lasofoxifene, novel selective estrogen receptor modulator with chemopreventive and therapeutic activity in the N-nitroso-N-methylurea-induced rat mammary tumor model. Cancer Res 61 24 (2001) 8683-8688
119. Robertson D.W., Katzenellenbogen J.A., Hayes J.R., and Katzenellenbogen B.S. Antiestrogen basicity-activity relationships: a comparison of the estrogen receptor binding and antiuterotrophic potencies of several analogues of (Z)-1,2 dipheny1-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-butene (tamoxifen Nolvadex) having altered basicity. J Med Chem 25 (1982) 167-171
120. Hellmann-Blumberg U., Taras T.L., Wurz G.T., and DeGregorio M.W. Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene. Breast Cancer Res Treat 60 1 (2000) 63-70
121. Qu Q., Zheng H., Dahllund J., Laine A., Cockcroft N., Peng Z., et al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 141 2 (2000) 809-820
122. DeGregorio M.W., Wurz G.T., Taras T.L., Erkkola R.U., Halonen K.H., and Huupponen R.K. Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator. Eur J Clin Pharmacol 56 6-7 (2000) 469-475
123. Rutanen E.M., Heikkinen J., Halonen K., Komi J., Lammintausta R., and Ylikorkala O. Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause 10 5 (2003) 433-439
124. Komi J., Lankinen K.S., Harkonen P., DeGregorio M.W., Voipio S., Kivinen S., et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause 12 2 (2005) 202-209
125. Namba R., Young L.J., Maglione J.E., McGoldrick E.T., Liu S., Wurz G.T., et al. Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ. Breast Cancer Res 7 6 (2005) R881-R889
126. Wurz G.T., Read K.C., Marchisano-Karpman C., Gregg J.P., Beckett L.A., Yu Q., et al. Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol 97 3 (2005) 230-240
127. Beverage J.N., Sissung T.M., Sion A.M., Danesi R., and Figg W.D. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 96 9 (2007) 2224-2231
128. Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3 2 (2002) 229-243
129. Raimundo S., Toscano C., Klein K., Fischer J., Griese E.U., Eichelbaum M., et al. A novel intronic mutation, 2988G > A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects. Clin Pharmacol Ther 76 2 (2004) 128-138
130. Hanioka N., Kimura S., Meyer U.A., and Gonzalez F.J. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934-a base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am J Hum Genet 47 6 (1990) 994-1001
131. Bernard S., Neville K.A., Nguyen A.T., and Flockhart D.A. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist 11 2 (2006) 126-135
132. Lim Y.C., Desta Z., Flockhart D.A., and Skaar T.C. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 55 (2005) 471-478
133. Lim Y.C., Li L., Desta Z., Zhao Q., Rae J.M., Flockhart D.A., et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 318 2 (2006) 503-512
134. Jin Y., Desta Z., Stearns V., Ward B., Ho H., Lee K.H., et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. JNCI 97 (2005) 30-39
135. Fisher B., Costantino J., Redmond C., Poisson R., Bowman D., Couture J., et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320 8 (1989) 479-484
136. Fisher B., Dignam J., Wolmark N., Wickerham D.L., Fisher E.R., Mamounas E., et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 9169 (1999) 1993-2000
137. Fisher B., Costantino J.P., Wickerham D.L., Redmond C.K., Kavanah M., Cronin W.M., et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (1998) 1371-1388
138. Loprinzi C.L., Kugler J.W., Sloan J.A., Mailliard J.A., LaVasseur B.I., Barton D.L., et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356 9247 (2000) 2059-2063
139. Loprinzi C.L., Sloan J.A., Perez E.A., Quella S.K., Stella P.J., Mailliard J.A., et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20 6 (2002) 1578-1583
140. Stearns V., Beebe K.L., Iyengar M., and Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 289 21 (2003) 2827-2834
141. Dehal S.S., and Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 57 16 (1997) 3402-3406
142. Crewe H.K., Ellis S.W., Lennard M.S., and Tucker G.T. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 53 2 (1997) 171-178
143. Coller J.K., Krebsfaenger N., Klein K., Endrizzi K., Wolbold R., Lang T., et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 54 2 (2002) 157-167
144. Lessard E., Yessine M.A., Hamelin B.A., Gauvin C., Labbe L., O'Hara G., et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 21 2 (2001) 175-184
145. Albers L.J., Reist C., Vu R.L., Fujimoto K., Ozdemir V., Helmeste D., et al. Effect of venlafaxine on imipramine metabolism. Psychiatry Res 96 3 (2000) 235-243
146. Yoon Y.R., Cha I.J., Shon J.H., Kim K.A., Cha Y.N., Jang I.J., et al. Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects. Clin Pharmacol Ther 67 5 (2000) 567-576
147. Jeppesen U., Gram L.F., Vistisen K., Loft S., Poulsen H.E., and Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 51 1 (1996) 73-78
148. Borges S., Desta Z., Li L., Skaar T.C., Ward B.A., Nguyen A., et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80 1 (2006) 61-74
149. Goetz M.P., Rae J.M., Suman V.J., Safgren S.L., Ames M.M., Visscher D.W., et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23 36 (2005) 9312-9318
150. Goetz M.P., Knox S.K., Suman V.J., Rae J.M., Safgren S.L., Ames M.M., et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101 1 (2007) 113-121
151. Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat 2007, doi:10.1007/s10549-007-9162X.
152. Nowell S., Sweeney C., Winters M., Stone A., Lang N.P., Hutchins L.F., et al. Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J Natl Cancer Inst 94 21 (2002) 1635-1640
153. Nowell S.A., Ahn J., Rae J.M., Scheys J.O., Trovato A., Sweeney C., et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91 3 (2005) 249-258
154. Wegman P.P., and Wingren S. CYP2D6 variants and the prediction of tamoxifen response in randomized patients: author response. Breast Cancer Res 7 6 (2005) E7
155. Wegman P., Elingarami S., Carstensen J., Stal O., Nordenskjold B., and Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9 1 (2007) R7